Disease Information

General Information of the Disease (ID: DIS00039)

• Name: Candidosis
• ICD: ICD-11: 1F23

Type(s) of Resistant Mechanism of This Disease

  ADTT: Aberration of the Drug's Therapeutic Target

  DISM: Drug Inactivation by Structure Modification

  IDUE: Irregularity in Drug Uptake and Drug Efflux

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 16 drug(s) in total

Amorolfine

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Pleiotropic ABC efflux transporter of multiple drugs CDR1 (CDR1) [1]

• Sensitive Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Molecule Alteration: Deletion mutation; Deleteion
• Sensitive Drug: Amorolfine
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain DSY448; 5476
• Experiment for Molecule Alteration: PCR; Southern blotting analysis; Northern blottling analysis
• Experiment for Drug Resistance: Growth differences between the different C. albicans strains assay
• Mechanism Description: The delta cdr1 mutant was also hypersusceptible to other antifungal agents (terbinafine and amorolfine) and to different metabolic inhibitors (cycloheximide, brefeldin A, and fluphenazine).

Amphotericin B

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Heat shock protein HSP 90 (HSP90 ) [2]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Amphotericin B
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Candida albicans strain; 5476
• Mechanism Description: The fitness and survival of amphotericin B-resistant Candida isolates are critically dependent upon Hsp90 expression and function. As a consequence, pharmacological inhibition of Hsp90 in resistant C. albicans or C. tropicalis strains abolished amphotericin B resistance.

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [2]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Molecule Alteration: Missense mutation; p.A114S
• Resistant Drug: Amphotericin B
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Candida albicans strain; 5476
• Mechanism Description: In C. albicans, reduced amphotericin B susceptibility can occur through mutations in several ergosterol biosynthesis enzymes, including ERG2,ERG3, ERG5, ERG11.

Key Molecule: Delta(7)-sterol 5(6)-desaturase ERG3 (ERG3) [2]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Molecule Alteration: Mutation; p.H243N+p.T330A+p.D147G
• Resistant Drug: Amphotericin B
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Candida albicans strain; 5476
• Mechanism Description: In C. albicans, reduced amphotericin B susceptibility can occur through mutations in several ergosterol biosynthesis enzymes, including ERG2,ERG3, ERG5, ERG11.

Key Molecule: C-22 sterol desaturase ERG5 (ERG5) [2]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Molecule Alteration: SNP; p.CA108
• Resistant Drug: Amphotericin B
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Candida albicans strain; 5476
• Mechanism Description: In C. albicans, reduced amphotericin B susceptibility can occur through mutations in several ergosterol biosynthesis enzymes, including ERG2,ERG3, ERG5, ERG11.

Anidulafungin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: D-glucan-1,3-beta--UDP glucosyltransferase (FKS1) [3]

• Resistant Disease: Candida auris infection [ICD-11: 1F23.2]
• Molecule Alteration: Missense mutation; p.S639P
• Resistant Drug: Anidulafungin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida auris strain; 498019
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Broth microdilution assay
• Mechanism Description: Sequencing of FkS revealed that 4 isolates contain the amino acid substitution S639P and those isolates exhibit the highest MICs to echinocandins (micafungin, caspofungin, and anidulafungin, CD101).

Key Molecule: D-glucan-1,3-beta--UDP glucosyltransferase (FKS1) [4]

• Resistant Disease: Candida auris infection [ICD-11: 1F23.2]
• Molecule Alteration: Missense mutation; p.S639F
• Resistant Drug: Anidulafungin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida auris strain; 498019
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: CLSI broth microdilution method assay
• Mechanism Description: Echinocandin (micafungin, caspofungin, and anidulafungin) resistance was linked to a novel mutation S639F in FkS1 hot spot region I.

Key Molecule: D-glucan-1,3-beta--UDP glucosyltransferase (FKS1) [5]

• Resistant Disease: Candida auris infection [ICD-11: 1F23.2]
• Molecule Alteration: Missense mutation; p.S652Y
• Resistant Drug: Anidulafungin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida auris strain; 498019
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: AFST assay
• Mechanism Description: One isolate displayed resistance to both echinocandins (micafungin, caspofungin, and anidulafungin) and 5-flucytosine; the former was associated with a serine to tyrosine amino acid substitution in the gene FkS1, and the latter was associated with a phenylalanine to isoleucine substitution in the gene FUR1.

Key Molecule: D-glucan-1,3-beta--UDP glucosyltransferase (FKS1) [6]

• Resistant Disease: Candida glabrata infection [ICD-11: 1F23.3]
• Molecule Alteration: Missense mutation; p.D632G (c.A1895G)
• Resistant Drug: Anidulafungin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida glabrata strain; 5478
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: NCCLS method M-27A with broth macrodilution techniques assay
• Mechanism Description: Fks1p and Fks2p amino acid substitutions confer reduced echinocandin susceptibility in C. glabrata.

Key Molecule: D-glucan-1,3-beta--UDP glucosyltransferase (FKS1) [6]

• Resistant Disease: Candida glabrata infection [ICD-11: 1F23.3]
• Molecule Alteration: Missense mutation; p.D632E (c.T1896G)
• Resistant Drug: Anidulafungin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida glabrata strain; 5478
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: NCCLS method M-27A with broth macrodilution techniques assay
• Mechanism Description: Recently, three reports showed that amino acid substitutions in Fks1p (D632E) and Fks2p (F659V) are responsible for clinical echinocandin resistance in C. glabrata.

Key Molecule: D-glucan-1,3-beta--UDP glucosyltransferase (FKS1) [6]

• Resistant Disease: Candida glabrata infection [ICD-11: 1F23.3]
• Molecule Alteration: Missense mutation; p.D632Y (c.G1894T)
• Resistant Drug: Anidulafungin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida glabrata strain; 5478
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: NCCLS method M-27A with broth macrodilution techniques assay
• Mechanism Description: Fks1p and Fks2p amino acid substitutions confer reduced echinocandin susceptibility in C. glabrata.

Key Molecule: D-glucan-1,3-beta--UDP glucosyltransferase (FKS1) [6]

• Resistant Disease: Candida glabrata infection [ICD-11: 1F23.3]
• Molecule Alteration: Missense mutation; p.F625S (c.T1874C)
• Resistant Drug: Anidulafungin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida glabrata strain; 5478
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: NCCLS method M-27A with broth macrodilution techniques assay
• Mechanism Description: Fks1p and Fks2p amino acid substitutions confer reduced echinocandin susceptibility in C. glabrata.

Key Molecule: D-glucan-1,3-beta--UDP glucosyltransferase (FKS1) [6]

• Resistant Disease: Candida glabrata infection [ICD-11: 1F23.3]
• Molecule Alteration: Missense mutation; p.S629P (c.T1885C)
• Resistant Drug: Anidulafungin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida glabrata strain; 5478
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: NCCLS method M-27A with broth macrodilution techniques assay
• Mechanism Description: Fks1p and Fks2p amino acid substitutions confer reduced echinocandin susceptibility in C. glabrata.

Key Molecule: D-glucan-1,3-beta--UDP glucosyltransferase (FKS1) [6]

• Resistant Disease: Candida glabrata infection [ICD-11: 1F23.3]
• Molecule Alteration: Missense mutation; p.F659V (c.T1975G)
• Resistant Drug: Anidulafungin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida glabrata strain; 5478
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: NCCLS method M-27A with broth macrodilution techniques assay
• Mechanism Description: Recently, three reports showed that amino acid substitutions in Fks1p (D632E) and Fks2p (F659V) are responsible for clinical echinocandin resistance in C. glabrata.

Key Molecule: D-glucan-1,3-beta--UDP glucosyltransferase (FKS1) [6]

• Resistant Disease: Candida glabrata infection [ICD-11: 1F23.3]
• Molecule Alteration: Missense mutation; p.F659S(c.T1976C)
• Resistant Drug: Anidulafungin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida glabrata strain; 5478
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: NCCLS method M-27A with broth macrodilution techniques assay
• Mechanism Description: Fks1p and Fks2p amino acid substitutions confer reduced echinocandin susceptibility in C. glabrata.

Key Molecule: D-glucan-1,3-beta--UDP glucosyltransferase (FKS1) [6]

• Resistant Disease: Candida glabrata infection [ICD-11: 1F23.3]
• Molecule Alteration: Frameshift mutation; p.F659del(c.1974-CTT-1976)
• Resistant Drug: Anidulafungin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida glabrata strain; 5478
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: NCCLS method M-27A with broth macrodilution techniques assay
• Mechanism Description: Fks1p and Fks2p amino acid substitutions confer reduced echinocandin susceptibility in C. glabrata.

Key Molecule: D-glucan-1,3-beta--UDP glucosyltransferase (FKS1) [6]

• Resistant Disease: Candida glabrata infection [ICD-11: 1F23.3]
• Molecule Alteration: Nonsense mutation; p.R1377STOP (c.A4129T)
• Resistant Drug: Anidulafungin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida glabrata strain; 5478
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: NCCLS method M-27A with broth macrodilution techniques assay
• Mechanism Description: Fks1p and Fks2p amino acid substitutions confer reduced echinocandin susceptibility in C. glabrata.

Key Molecule: D-glucan-1,3-beta--UDP glucosyltransferase (FKS1) [7]

• Resistant Disease: Candida krusei infection [ICD-11: 1F23.4]
• Molecule Alteration: Missense mutation; p.F655C
• Resistant Drug: Anidulafungin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida krusei strain; 4909
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Broth macrodilution assay
• Mechanism Description: A Candida krusei strain from a patient with acute myelogenous leukemia that displayed reduced susceptibility to echinocandin drugs contained a heterozygous mutation, T2080k, in FkS1. The resulting Phe655-Cys substitution altered the sensitivity of glucan synthase to echinocandin drugs, consistent with a common mechanism for echinocandin resistance in Candida spp.

Key Molecule: D-glucan-1,3-beta--UDP glucosyltransferase (FKS1) [8]

• Resistant Disease: Invasive candidiasis [ICD-11: 1F23.5]
• Molecule Alteration: Missense mutation; p.P660A
• Resistant Drug: Anidulafungin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida parapsilosis strain; 5480
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: M27-A2 broth dilution method assay
• Mechanism Description: Overall, these data firmly indicate that a naturally occurring P660A substitution in Fks1p from the C. parapsilosis group accounts for the reduced susceptibility phenotype.

Caspofungin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: D-glucan-1,3-beta--UDP glucosyltransferase (FKS1) [9]

• Resistant Disease: Candida albicans infection [ICD-11: 1F23.Y]
• Molecule Alteration: Missense mutation; p.S645Y
• Resistant Drug: Caspofungin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida tropicalis strain NR3; 5482
• In Vivo Model: DBA/2J murine model of disseminated candidiasis; DBA/2N murine model of disseminated candidiasis; Mus musculus
• Experiment for Molecule Alteration: Site-directed mutagenesis; MLST assay
• Experiment for Drug Resistance: Liquid broth microdilution assay
• Mechanism Description: One group of amino acid substitutions, in the Fks proteins of S. cerevisiae (F639I, V641k, D646Y) and C. albicans (S645F, S645P, S645Y), maps to a short conserved region of ScFks1p and CaFks1p, which lead to caspofungin resistance in the S. cerevisiae and C. albicans as well as C.krusei.

Key Molecule: D-glucan-1,3-beta--UDP glucosyltransferase (FKS1) [9]

• Resistant Disease: Candida albicans infection [ICD-11: 1F23.Y]
• Molecule Alteration: Missense mutation; p.S645F
• Resistant Drug: Caspofungin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain; 5476
• In Vivo Model: DBA/2J murine model of disseminated candidiasis; DBA/2N murine model of disseminated candidiasis; Mus musculus
• Experiment for Molecule Alteration: Site-directed mutagenesis; MLST assay
• Experiment for Drug Resistance: Liquid broth microdilution assay
• Mechanism Description: One group of amino acid substitutions, in the Fks proteins of S. cerevisiae (F639I, V641k, D646Y) and C. albicans (S645F, S645P, S645Y), maps to a short conserved region of ScFks1p and CaFks1p, which lead to caspofungin resistance in the S. cerevisiae and C. albicans as well as C.krusei.

Key Molecule: D-glucan-1,3-beta--UDP glucosyltransferase (FKS1) [10]

• Resistant Disease: Candida albicans infection [ICD-11: 1F23.Y]
• Molecule Alteration: Missense mutation; p.S645P
• Resistant Drug: Caspofungin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain; 5476
• Experiment for Molecule Alteration: NGS sequencing assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Amino acid changes in FkS1 may contribute to Candida albicans emerging caspofungin resistance.

Key Molecule: D-glucan-1,3-beta--UDP glucosyltransferase (FKS1) [3]

• Resistant Disease: Candida auris infection [ICD-11: 1F23.2]
• Molecule Alteration: Missense mutation; p.S639P
• Resistant Drug: Caspofungin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida auris strain; 498019
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Broth microdilution assay
• Mechanism Description: Sequencing of FkS revealed that 4 isolates contain the amino acid substitution S639P and those isolates exhibit the highest MICs to echinocandins (micafungin, caspofungin, and anidulafungin, CD101).

Key Molecule: D-glucan-1,3-beta--UDP glucosyltransferase (FKS1) [4]

• Resistant Disease: Candida auris infection [ICD-11: 1F23.2]
• Molecule Alteration: Missense mutation; p.S639F
• Resistant Drug: Caspofungin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida auris strain; 498019
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: CLSI broth microdilution method assay
• Mechanism Description: Echinocandin (micafungin, caspofungin, and anidulafungin) resistance was linked to a novel mutation S639F in FkS1 hot spot region I.

Key Molecule: D-glucan-1,3-beta--UDP glucosyltransferase (FKS1) [5]

• Resistant Disease: Candida auris infection [ICD-11: 1F23.2]
• Molecule Alteration: Missense mutation; p.S652Y
• Resistant Drug: Caspofungin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida auris strain; 498019
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: AFST assay
• Mechanism Description: One isolate displayed resistance to both echinocandins (micafungin, caspofungin, and anidulafungin) and 5-flucytosine; the former was associated with a serine to tyrosine amino acid substitution in the gene FkS1, and the latter was associated with a phenylalanine to isoleucine substitution in the gene FUR1.

Key Molecule: D-glucan-1,3-beta--UDP glucosyltransferase (FKS1) [6]

• Resistant Disease: Candida glabrata infection [ICD-11: 1F23.3]
• Molecule Alteration: Missense mutation; p.D632G (c.A1895G)
• Resistant Drug: Caspofungin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida glabrata strain; 5478
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: NCCLS method M-27A with broth macrodilution techniques assay
• Mechanism Description: Fks1p and Fks2p amino acid substitutions confer reduced echinocandin susceptibility in C. glabrata.

Key Molecule: D-glucan-1,3-beta--UDP glucosyltransferase (FKS1) [6]

• Resistant Disease: Candida glabrata infection [ICD-11: 1F23.3]
• Molecule Alteration: Missense mutation; p.D632E (c.T1896G)
• Resistant Drug: Caspofungin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida glabrata strain; 5478
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: NCCLS method M-27A with broth macrodilution techniques assay
• Mechanism Description: Recently, three reports showed that amino acid substitutions in Fks1p (D632E) and Fks2p (F659V) are responsible for clinical echinocandin resistance in C. glabrata.

Key Molecule: D-glucan-1,3-beta--UDP glucosyltransferase (FKS1) [6]

• Resistant Disease: Candida glabrata infection [ICD-11: 1F23.3]
• Molecule Alteration: Missense mutation; p.D632Y (c.G1894T)
• Resistant Drug: Caspofungin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida glabrata strain; 5478
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: NCCLS method M-27A with broth macrodilution techniques assay
• Mechanism Description: Fks1p and Fks2p amino acid substitutions confer reduced echinocandin susceptibility in C. glabrata.

Key Molecule: D-glucan-1,3-beta--UDP glucosyltransferase (FKS1) [6]

• Resistant Disease: Candida glabrata infection [ICD-11: 1F23.3]
• Molecule Alteration: Missense mutation; p.F625S (c.T1874C)
• Resistant Drug: Caspofungin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida glabrata strain; 5478
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: NCCLS method M-27A with broth macrodilution techniques assay
• Mechanism Description: Fks1p and Fks2p amino acid substitutions confer reduced echinocandin susceptibility in C. glabrata.

Key Molecule: D-glucan-1,3-beta--UDP glucosyltransferase (FKS1) [6]

• Resistant Disease: Candida glabrata infection [ICD-11: 1F23.3]
• Molecule Alteration: Missense mutation; p.S629P (c.T1885C)
• Resistant Drug: Caspofungin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida glabrata strain; 5478
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: NCCLS method M-27A with broth macrodilution techniques assay
• Mechanism Description: Fks1p and Fks2p amino acid substitutions confer reduced echinocandin susceptibility in C. glabrata.

Key Molecule: D-glucan-1,3-beta--UDP glucosyltransferase (FKS1) [6]

• Resistant Disease: Candida glabrata infection [ICD-11: 1F23.3]
• Molecule Alteration: Missense mutation; p.F659V (c.T1975G)
• Resistant Drug: Caspofungin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida glabrata strain; 5478
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: NCCLS method M-27A with broth macrodilution techniques assay
• Mechanism Description: Recently, three reports showed that amino acid substitutions in Fks1p (D632E) and Fks2p (F659V) are responsible for clinical echinocandin resistance in C. glabrata.

Key Molecule: D-glucan-1,3-beta--UDP glucosyltransferase (FKS1) [6]

• Resistant Disease: Candida glabrata infection [ICD-11: 1F23.3]
• Molecule Alteration: Missense mutation; p.F659S (c.T1976C)
• Resistant Drug: Caspofungin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida glabrata strain; 5478
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: NCCLS method M-27A with broth macrodilution techniques assay
• Mechanism Description: Fks1p and Fks2p amino acid substitutions confer reduced echinocandin susceptibility in C. glabrata.

Key Molecule: D-glucan-1,3-beta--UDP glucosyltransferase (FKS1) [6]

• Resistant Disease: Candida glabrata infection [ICD-11: 1F23.3]
• Molecule Alteration: Missense mutation; p.F659del (c.1974-CTT-1976)
• Resistant Drug: Caspofungin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida glabrata strain; 5478
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: NCCLS method M-27A with broth macrodilution techniques assay
• Mechanism Description: Fks1p and Fks2p amino acid substitutions confer reduced echinocandin susceptibility in C. glabrata.

Key Molecule: D-glucan-1,3-beta--UDP glucosyltransferase (FKS1) [6]

• Resistant Disease: Candida glabrata infection [ICD-11: 1F23.3]
• Molecule Alteration: Nonsense mutation; p.R1377STOP (c.A4129T)
• Resistant Drug: Caspofungin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida glabrata strain; 5478
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: NCCLS method M-27A with broth macrodilution techniques assay
• Mechanism Description: Fks1p and Fks2p amino acid substitutions confer reduced echinocandin susceptibility in C. glabrata.

Key Molecule: D-glucan-1,3-beta--UDP glucosyltransferase (FKS1) [9]

• Resistant Disease: Candida krusei infection [ICD-11: 1F23.4]
• Molecule Alteration: Missense mutation; p.R1361G
• Resistant Drug: Caspofungin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida krusei strain; 4909
• In Vivo Model: CD-1 murine model of disseminated candidiasis; Mus musculus
• Experiment for Molecule Alteration: Site-directed mutagenesis; MLST assay
• Experiment for Drug Resistance: Liquid broth microdilution assay
• Mechanism Description: One group of amino acid substitutions, in the Fks proteins of S. cerevisiae (F639I, V641k, D646Y) and C. albicans (S645F, S645P, S645Y), maps to a short conserved region of ScFks1p and CaFks1p, which lead to caspofungin resistance in the S. cerevisiae and C. albicans as well as C.krusei.

Key Molecule: D-glucan-1,3-beta--UDP glucosyltransferase (FKS1) [7]

• Resistant Disease: Candida krusei infection [ICD-11: 1F23.4]
• Molecule Alteration: Missense mutation; p.F655C
• Resistant Drug: Caspofungin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida krusei strain; 4909
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Broth macrodilution assay
• Mechanism Description: A Candida krusei strain from a patient with acute myelogenous leukemia that displayed reduced susceptibility to echinocandin drugs contained a heterozygous mutation, T2080k, in FkS1. The resulting Phe655-Cys substitution altered the sensitivity of glucan synthase to echinocandin drugs, consistent with a common mechanism for echinocandin resistance in Candida spp.

Key Molecule: D-glucan-1,3-beta--UDP glucosyltransferase (FKS1) [8]

• Resistant Disease: Invasive candidiasis [ICD-11: 1F23.5]
• Molecule Alteration: Missense mutation; p.P660A
• Resistant Drug: Caspofungin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida parapsilosis strain; 5480
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: M27-A2 broth dilution method assay
• Mechanism Description: Overall, these data firmly indicate that a naturally occurring P660A substitution in Fks1p from the C. parapsilosis group accounts for the reduced susceptibility phenotype.

Fluconazole

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [11], [12]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Molecule Alteration: Missense mutation; p.S405F
• Resistant Drug: Fluconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain C470; 5476
• In Vitro Model: Candida albicans strain C478; 5476
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Broth microdilution assay
• Mechanism Description: Seventeen of the 38 isolates analyzed exhibited cross-resistance to fluconazole (MIC, >=64 ug/ml) and voriconazole (in the absence of established breakpoints, we labeled an isolate resistant to voriconazole if the MIC was >1 ug/ml). Sixteen of the 17 isolates (the exception was C587) exhibited the same pattern of mutations in ERG11; a substitution close to the N terminus of the protein (k128T, Y132H, or Y257H) together with a substitution towards the C terminus of the protein (G405F, G448V, G450E, or G464S).

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [11], [12]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Molecule Alteration: Missense mutation; p.G464S
• Resistant Drug: Fluconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain C587; 5476
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Broth microdilution assay
• Mechanism Description: Seventeen of the 38 isolates analyzed exhibited cross-resistance to fluconazole (MIC, >=64 ug/ml) and voriconazole (in the absence of established breakpoints, we labeled an isolate resistant to voriconazole if the MIC was >1 ug/ml). Sixteen of the 17 isolates (the exception was C587) exhibited the same pattern of mutations in ERG11; a substitution close to the N terminus of the protein (k128T, Y132H, or Y257H) together with a substitution towards the C terminus of the protein (G405F, G448V, G450E, or G464S).

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [13]

• Resistant Disease: Candida albicans infection [ICD-11: 1F23.Y]
• Molecule Alteration: Missense mutation; p.A114S+p.Y257H+p.G487T+p.T916C
• Resistant Drug: Fluconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain; 5476
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: M27-A2 broth dilution method assay
• Mechanism Description: Amino acid changes in ERG11 may contribute to Candida albicans emerging fluconazole resistance.

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [13]

• Resistant Disease: Candida albicans infection [ICD-11: 1F23.Y]
• Molecule Alteration: Missense mutation; p.M140R
• Resistant Drug: Fluconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain; 5476
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: M27-A2 broth dilution method assay
• Mechanism Description: Amino acid changes in ERG11 may contribute to Candida albicans emerging fluconazole resistance.

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [13]

• Resistant Disease: Candida albicans infection [ICD-11: 1F23.Y]
• Molecule Alteration: Missense mutation; p.K161N
• Resistant Drug: Fluconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain; 5476
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: M27-A2 broth dilution method assay
• Mechanism Description: Amino acid changes in ERG11 may contribute to Candida albicans emerging fluconazole resistance.

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [13]

• Resistant Disease: Candida albicans infection [ICD-11: 1F23.Y]
• Molecule Alteration: Missense mutation; p.R163T
• Resistant Drug: Fluconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain; 5476
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: M27-A2 broth dilution method assay
• Mechanism Description: Amino acid changes in ERG11 may contribute to Candida albicans emerging fluconazole resistance.

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [13]

• Resistant Disease: Candida albicans infection [ICD-11: 1F23.Y]
• Molecule Alteration: Missense mutation; p.E165K
• Resistant Drug: Fluconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain; 5476
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: M27-A2 broth dilution method assay
• Mechanism Description: Amino acid changes in ERG11 may contribute to Candida albicans emerging fluconazole resistance.

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [13]

• Resistant Disease: Candida albicans infection [ICD-11: 1F23.Y]
• Molecule Alteration: Missense mutation; p.D225Y
• Resistant Drug: Fluconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain; 5476
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: M27-A2 broth dilution method assay
• Mechanism Description: Amino acid changes in ERG11 may contribute to Candida albicans emerging fluconazole resistance.

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [13]

• Resistant Disease: Candida albicans infection [ICD-11: 1F23.Y]
• Molecule Alteration: Missense mutation; p.D225H
• Resistant Drug: Fluconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain; 5476
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: M27-A2 broth dilution method assay
• Mechanism Description: Amino acid changes in ERG11 may contribute to Candida albicans emerging fluconazole resistance.

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [13]

• Resistant Disease: Candida albicans infection [ICD-11: 1F23.Y]
• Molecule Alteration: Missense mutation; p.F449Y
• Resistant Drug: Fluconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain; 5476
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: M27-A2 broth dilution method assay
• Mechanism Description: Amino acid changes in ERG11 may contribute to Candida albicans emerging fluconazole resistance.

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [13]

• Resistant Disease: Candida albicans infection [ICD-11: 1F23.Y]
• Molecule Alteration: Missense mutation; p.I471T
• Resistant Drug: Fluconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain; 5476
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: M27-A2 broth dilution method assay
• Mechanism Description: Amino acid changes in ERG11 may contribute to Candida albicans emerging fluconazole resistance.

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [13]

• Resistant Disease: Candida albicans infection [ICD-11: 1F23.Y]
• Molecule Alteration: Missense mutation; p.Q474K
• Resistant Drug: Fluconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain; 5476
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: M27-A2 broth dilution method assay
• Mechanism Description: Amino acid changes in ERG11 may contribute to Candida albicans emerging fluconazole resistance.

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [13]

• Resistant Disease: Candida albicans infection [ICD-11: 1F23.Y]
• Molecule Alteration: Missense mutation; p.P375Q
• Resistant Drug: Fluconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain; 5476
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: M27-A2 broth dilution method assay
• Mechanism Description: Amino acid changes in ERG11 may contribute to Candida albicans emerging fluconazole resistance.

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [13]

• Resistant Disease: Candida albicans infection [ICD-11: 1F23.Y]
• Molecule Alteration: Missense mutation; p.R381I
• Resistant Drug: Fluconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain; 5476
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: M27-A2 broth dilution method assay
• Mechanism Description: Amino acid changes in ERG11 may contribute to Candida albicans emerging fluconazole resistance.

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [13]

• Resistant Disease: Candida albicans infection [ICD-11: 1F23.Y]
• Molecule Alteration: Missense mutation; p.K119N
• Resistant Drug: Fluconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain; 5476
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: M27-A2 broth dilution method assay
• Mechanism Description: Amino acid changes in ERG11 may contribute to Candida albicans emerging fluconazole resistance.

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [14]

• Resistant Disease: Candida albicans infection [ICD-11: 1F23.Y]
• Molecule Alteration: Missense mutation; p.Y132F+p.Y205E+p.Y257H+p.D116E+p.K143Q
• Resistant Drug: Fluconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain; 5476
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: M27-A2 broth dilution method assay
• Mechanism Description: We observed that substitutions A114S, Y132H, Y132F, k143R, Y257H, and a new k143Q substitution contributed to significant increases ( fourfold) in fluconazole and voriconazole resistance; changes in itraconazole resistance were not significant (twofold).

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [14]

• Resistant Disease: Candida albicans infection [ICD-11: 1F23.Y]
• Molecule Alteration: Missense mutation; p.Y132F+p.Y205E+p.V437I+p.D116E+p.K143Q
• Resistant Drug: Fluconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain; 5476
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: M27-A2 broth dilution method assay
• Mechanism Description: We observed that substitutions A114S, Y132H, Y132F, k143R, Y257H, and a new k143Q substitution contributed to significant increases ( fourfold) in fluconazole and voriconazole resistance; changes in itraconazole resistance were not significant (twofold).

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [15]

• Resistant Disease: Candida auris infection [ICD-11: 1F23.2]
• Molecule Alteration: Missense mutation; p.Y132F
• Resistant Drug: Fluconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida auris strain; 498019
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Three additional hot-spot amino acid substitutions were identified that have been either proposed or proved to significantly increase fluconazole resistance in C. albicans. These substitutions were strongly associated with geographic clades: F126T with South Africa, Y132F with Venezuela, and Y132F or k143R with India and Pakistan.

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [15]

• Resistant Disease: Candida auris infection [ICD-11: 1F23.2]
• Molecule Alteration: Missense mutation; p.K143R
• Resistant Drug: Fluconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida auris strain; 498019
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Three additional hot-spot amino acid substitutions were identified that have been either proposed or proved to significantly increase fluconazole resistance in C. albicans. These substitutions were strongly associated with geographic clades: F126T with South Africa, Y132F with Venezuela, and Y132F or k143R with India and Pakistan.

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [15]

• Resistant Disease: Candida auris infection [ICD-11: 1F23.2]
• Molecule Alteration: Missense mutation; p.F126T
• Resistant Drug: Fluconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida auris strain; 498019
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Three additional hot-spot amino acid substitutions were identified that have been either proposed or proved to significantly increase fluconazole resistance in C. albicans. These substitutions were strongly associated with geographic clades: F126T with South Africa, Y132F with Venezuela, and Y132F or k143R with India and Pakistan.

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [4]

• Resistant Disease: Candida auris infection [ICD-11: 1F23.2]
• Molecule Alteration: Missense mutation; p.Y132F
• Resistant Drug: Fluconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida auris strain; 498019
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: CLSI broth microdilution method assay
• Mechanism Description: Notably, Y132F and k143R substitutions responsible for azole resistance in C. albicans were observed in all 34 (77%) sequenced strains that were fluconazole resistant (MICs 32 to >=64 mg/L).

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [4]

• Resistant Disease: Candida auris infection [ICD-11: 1F23.2]
• Molecule Alteration: Missense mutation; p.K143R
• Resistant Drug: Fluconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida auris strain; 498019
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: CLSI broth microdilution method assay
• Mechanism Description: Notably, Y132F and k143R substitutions responsible for azole resistance in C. albicans were observed in all 34 (77%) sequenced strains that were fluconazole resistant (MICs 32 to >=64 mg/L).

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [16]

• Resistant Disease: Candida krusei infection [ICD-11: 1F23.4]
• Molecule Alteration: Missense mutation; p.Y132F
• Resistant Drug: Fluconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida tropicalis strain; 5482
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Disk diffusion method assay
• Mechanism Description: Overexpression of CtERG11 associated with a missense mutation in this gene seemed to be responsible for the acquired azole resistance of this clinical isolate.

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [17]

• Resistant Disease: Candidosis [ICD-11: 1F23.0]
• Molecule Alteration: Missense mutation; p.F380S
• Resistant Drug: Fluconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: South America Candida albicans strain; 5476
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: The mutations identified in C. albicans fluconazole-resistant isolates indicate that azole resistance in fungi develops in protein regions involved in orchestrating the passage of CYP51p through different conformational stages rather than in residues directly contacting the triazole.

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [17]

• Resistant Disease: Candidosis [ICD-11: 1F23.0]
• Molecule Alteration: Missense mutation; p.Y132F+p.F145L
• Resistant Drug: Fluconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: South America Candida albicans strain; 5476
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: The mutations identified in C. albicans fluconazole-resistant isolates indicate that azole resistance in fungi develops in protein regions involved in orchestrating the passage of CYP51p through different conformational stages rather than in residues directly contacting the triazole.

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [17]

• Resistant Disease: Candidosis [ICD-11: 1F23.0]
• Molecule Alteration: Missense mutation; p.Y79C+p.T199I
• Resistant Drug: Fluconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: South America Candida albicans strain; 5476
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: The mutations identified in C. albicans fluconazole-resistant isolates indicate that azole resistance in fungi develops in protein regions involved in orchestrating the passage of CYP51p through different conformational stages rather than in residues directly contacting the triazole.

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [17]

• Resistant Disease: Candidosis [ICD-11: 1F23.0]
• Molecule Alteration: Missense mutation; p.V437I+p.I253V
• Resistant Drug: Fluconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: South America Candida albicans strain; 5476
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: The mutations identified in C. albicans fluconazole-resistant isolates indicate that azole resistance in fungi develops in protein regions involved in orchestrating the passage of CYP51p through different conformational stages rather than in residues directly contacting the triazole.

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [17]

• Resistant Disease: Candidosis [ICD-11: 1F23.0]
• Molecule Alteration: Missense mutation; p.E266D+p.V488I+p.V130I
• Resistant Drug: Fluconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: South America Candida albicans strain; 5476
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: The mutations identified in C. albicans fluconazole-resistant isolates indicate that azole resistance in fungi develops in protein regions involved in orchestrating the passage of CYP51p through different conformational stages rather than in residues directly contacting the triazole.

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [17]

• Resistant Disease: Candidosis [ICD-11: 1F23.0]
• Molecule Alteration: Missense mutation; p.K143E+p.P503L
• Resistant Drug: Fluconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: South America Candida albicans strain; 5476
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: The mutations identified in C. albicans fluconazole-resistant isolates indicate that azole resistance in fungi develops in protein regions involved in orchestrating the passage of CYP51p through different conformational stages rather than in residues directly contacting the triazole.

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [17]

• Resistant Disease: Candidosis [ICD-11: 1F23.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Fluconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: South America Candida albicans strain; 5476
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Overexpression of the genes ERG11, CDR1, CDR2, MDR1, and FLU1 has been linked to fluconazole resistance (White et al., 1998) and was investigated as a mechanism of resistance in our clinical isolates by using real-time RT-PCR.

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [12]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Molecule Alteration: Missense mutation; p.G464S+p.R467K
• Resistant Drug: Fluconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain; 5476
• Experiment for Molecule Alteration: Gene Sequencing asay; RFLP assay; Immunoblotting assay
• Experiment for Drug Resistance: Disk diffusion assays; Microbroth dilution MIC assay
• Mechanism Description: Site-directed mutagenesis of a wild-type CYP51A1 gene was performed to estimate the effect of each of these mutations on resistance to azole derivatives. Each single mutation, with the exception of G129A, had a measurable effect on the affinity of the target enzyme for specific azole derivatives.

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [12]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Molecule Alteration: Missense mutation; p.G464S+p.G129A
• Resistant Drug: Fluconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain; 5476
• Experiment for Molecule Alteration: Gene Sequencing asay; RFLP assay; Immunoblotting assay
• Experiment for Drug Resistance: Disk diffusion assays; Microbroth dilution MIC assay
• Mechanism Description: Site-directed mutagenesis of a wild-type CYP51A1 gene was performed to estimate the effect of each of these mutations on resistance to azole derivatives. Each single mutation, with the exception of G129A, had a measurable effect on the affinity of the target enzyme for specific azole derivatives.

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [12]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Molecule Alteration: Missense mutation; p.Y132H
• Resistant Drug: Fluconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain; 5476
• Experiment for Molecule Alteration: Gene Sequencing asay; RFLP assay; Immunoblotting assay
• Experiment for Drug Resistance: Disk diffusion assays; Microbroth dilution MIC assay
• Mechanism Description: Site-directed mutagenesis of a wild-type CYP51A1 gene was performed to estimate the effect of each of these mutations on resistance to azole derivatives. Each single mutation, with the exception of G129A, had a measurable effect on the affinity of the target enzyme for specific azole derivatives.

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [12]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Molecule Alteration: Missense mutation; p.S405F+p.Y132H
• Resistant Drug: Fluconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain; 5476
• Experiment for Molecule Alteration: Gene Sequencing asay; RFLP assay; Immunoblotting assay
• Experiment for Drug Resistance: Disk diffusion assays; Microbroth dilution MIC assay
• Mechanism Description: Site-directed mutagenesis of a wild-type CYP51A1 gene was performed to estimate the effect of each of these mutations on resistance to azole derivatives. Each single mutation, with the exception of G129A, had a measurable effect on the affinity of the target enzyme for specific azole derivatives.

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [12]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Molecule Alteration: Missense mutation; p.G464S+p.Y132H
• Resistant Drug: Fluconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain; 5476
• Experiment for Molecule Alteration: Gene Sequencing asay; RFLP assay; Immunoblotting assay
• Experiment for Drug Resistance: Disk diffusion assays; Microbroth dilution MIC assay
• Mechanism Description: Site-directed mutagenesis of a wild-type CYP51A1 gene was performed to estimate the effect of each of these mutations on resistance to azole derivatives. Each single mutation, with the exception of G129A, had a measurable effect on the affinity of the target enzyme for specific azole derivatives.

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [12]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Molecule Alteration: Missense mutation; p.R467K
• Resistant Drug: Fluconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain YkkB-13; 5476
• Experiment for Molecule Alteration: Gene Sequencing asay; RFLP assay; Immunoblotting assay
• Experiment for Drug Resistance: Disk diffusion assays; Microbroth dilution MIC assay
• Mechanism Description: Site-directed mutagenesis of a wild-type CYP51A1 gene was performed to estimate the effect of each of these mutations on resistance to azole derivatives. Each single mutation, with the exception of G129A, had a measurable effect on the affinity of the target enzyme for specific azole derivatives.

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [11]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Molecule Alteration: Missense mutation; p.Y132H+p.G450E
• Resistant Drug: Fluconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain C572; 5476
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Broth microdilution assay
• Mechanism Description: Seventeen of the 38 isolates analyzed exhibited cross-resistance to fluconazole (MIC, >=64 ug/ml) and voriconazole (in the absence of established breakpoints, we labeled an isolate resistant to voriconazole if the MIC was >1 ug/ml). Sixteen of the 17 isolates (the exception was C587) exhibited the same pattern of mutations in ERG11; a substitution close to the N terminus of the protein (k128T, Y132H, or Y257H) together with a substitution towards the C terminus of the protein (G405F, G448V, G450E, or G464S).

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [11]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Molecule Alteration: Missense mutation; p.G450E+p.G464S
• Resistant Drug: Fluconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain C530; 5476
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Broth microdilution assay
• Mechanism Description: Seventeen of the 38 isolates analyzed exhibited cross-resistance to fluconazole (MIC, >=64 ug/ml) and voriconazole (in the absence of established breakpoints, we labeled an isolate resistant to voriconazole if the MIC was >1 ug/ml). Sixteen of the 17 isolates (the exception was C587) exhibited the same pattern of mutations in ERG11; a substitution close to the N terminus of the protein (k128T, Y132H, or Y257H) together with a substitution towards the C terminus of the protein (G405F, G448V, G450E, or G464S).

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [11]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Molecule Alteration: Missense mutation; p.Y132H+p.G448V
• Resistant Drug: Fluconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain C535; 5476
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Broth microdilution assay
• Mechanism Description: Seventeen of the 38 isolates analyzed exhibited cross-resistance to fluconazole (MIC, >=64 ug/ml) and voriconazole (in the absence of established breakpoints, we labeled an isolate resistant to voriconazole if the MIC was >1 ug/ml). Sixteen of the 17 isolates (the exception was C587) exhibited the same pattern of mutations in ERG11; a substitution close to the N terminus of the protein (k128T, Y132H, or Y257H) together with a substitution towards the C terminus of the protein (G405F, G448V, G450E, or G464S).

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [11]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Molecule Alteration: Missense mutation; p.K128T+p.V452A
• Resistant Drug: Fluconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain C497; 5476
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Broth microdilution assay
• Mechanism Description: Seventeen of the 38 isolates analyzed exhibited cross-resistance to fluconazole (MIC, >=64 ug/ml) and voriconazole (in the absence of established breakpoints, we labeled an isolate resistant to voriconazole if the MIC was >1 ug/ml). Sixteen of the 17 isolates (the exception was C587) exhibited the same pattern of mutations in ERG11; a substitution close to the N terminus of the protein (k128T, Y132H, or Y257H) together with a substitution towards the C terminus of the protein (G405F, G448V, G450E, or G464S).

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [11]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Molecule Alteration: Missense mutation; p.Y132H+p.S405F
• Resistant Drug: Fluconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain C600; 5476
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Broth microdilution assay
• Mechanism Description: Seventeen of the 38 isolates analyzed exhibited cross-resistance to fluconazole (MIC, >=64 ug/ml) and voriconazole (in the absence of established breakpoints, we labeled an isolate resistant to voriconazole if the MIC was >1 ug/ml). Sixteen of the 17 isolates (the exception was C587) exhibited the same pattern of mutations in ERG11; a substitution close to the N terminus of the protein (k128T, Y132H, or Y257H) together with a substitution towards the C terminus of the protein (G405F, G448V, G450E, or G464S).

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [11]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Molecule Alteration: Missense mutation; p.G464S+p.K128T+p.R467I
• Resistant Drug: Fluconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain C477; 5476
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Broth microdilution assay
• Mechanism Description: Seventeen of the 38 isolates analyzed exhibited cross-resistance to fluconazole (MIC, >=64 ug/ml) and voriconazole (in the absence of established breakpoints, we labeled an isolate resistant to voriconazole if the MIC was >1 ug/ml). Sixteen of the 17 isolates (the exception was C587) exhibited the same pattern of mutations in ERG11; a substitution close to the N terminus of the protein (k128T, Y132H, or Y257H) together with a substitution towards the C terminus of the protein (G405F, G448V, G450E, or G464S).

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [11]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Molecule Alteration: Missense mutation; p.Y257H+p.G464S
• Resistant Drug: Fluconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain C438; 5476
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Broth microdilution assay
• Mechanism Description: Seventeen of the 38 isolates analyzed exhibited cross-resistance to fluconazole (MIC, >=64 ug/ml) and voriconazole (in the absence of established breakpoints, we labeled an isolate resistant to voriconazole if the MIC was >1 ug/ml). Sixteen of the 17 isolates (the exception was C587) exhibited the same pattern of mutations in ERG11; a substitution close to the N terminus of the protein (k128T, Y132H, or Y257H) together with a substitution towards the C terminus of the protein (G405F, G448V, G450E, or G464S).

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [11]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Molecule Alteration: Missense mutation; p.A61V+p.Y257H+p.G464S+p.G307S
• Resistant Drug: Fluconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain C440; 5476
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Broth microdilution assay
• Mechanism Description: Seventeen of the 38 isolates analyzed exhibited cross-resistance to fluconazole (MIC, >=64 ug/ml) and voriconazole (in the absence of established breakpoints, we labeled an isolate resistant to voriconazole if the MIC was >1 ug/ml). Sixteen of the 17 isolates (the exception was C587) exhibited the same pattern of mutations in ERG11; a substitution close to the N terminus of the protein (k128T, Y132H, or Y257H) together with a substitution towards the C terminus of the protein (G405F, G448V, G450E, or G464S).

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [11]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Molecule Alteration: Missense mutation; p.Y257H+p.G464S+p.G307S
• Resistant Drug: Fluconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain C439; 5476
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Broth microdilution assay
• Mechanism Description: Seventeen of the 38 isolates analyzed exhibited cross-resistance to fluconazole (MIC, >=64 ug/ml) and voriconazole (in the absence of established breakpoints, we labeled an isolate resistant to voriconazole if the MIC was >1 ug/ml). Sixteen of the 17 isolates (the exception was C587) exhibited the same pattern of mutations in ERG11; a substitution close to the N terminus of the protein (k128T, Y132H, or Y257H) together with a substitution towards the C terminus of the protein (G405F, G448V, G450E, or G464S).

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [11]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Molecule Alteration: Missense mutation; p.K143R
• Resistant Drug: Fluconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain C441; 5476
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Broth microdilution assay
• Mechanism Description: Seventeen of the 38 isolates analyzed exhibited cross-resistance to fluconazole (MIC, >=64 ug/ml) and voriconazole (in the absence of established breakpoints, we labeled an isolate resistant to voriconazole if the MIC was >1 ug/ml). Sixteen of the 17 isolates (the exception was C587) exhibited the same pattern of mutations in ERG11; a substitution close to the N terminus of the protein (k128T, Y132H, or Y257H) together with a substitution towards the C terminus of the protein (G405F, G448V, G450E, or G464S).

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [11]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Molecule Alteration: Missense mutation; p.Y257H+p.Y132H+p.E266D
• Resistant Drug: Fluconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain C489; 5476
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Broth microdilution assay
• Mechanism Description: Seventeen of the 38 isolates analyzed exhibited cross-resistance to fluconazole (MIC, >=64 ug/ml) and voriconazole (in the absence of established breakpoints, we labeled an isolate resistant to voriconazole if the MIC was >1 ug/ml). Sixteen of the 17 isolates (the exception was C587) exhibited the same pattern of mutations in ERG11; a substitution close to the N terminus of the protein (k128T, Y132H, or Y257H) together with a substitution towards the C terminus of the protein (G405F, G448V, G450E, or G464S).

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [11]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Molecule Alteration: Missense mutation; p.Y132H+p.G464S+p.H283R
• Resistant Drug: Fluconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain C507; 5476
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Broth microdilution assay
• Mechanism Description: Seventeen of the 38 isolates analyzed exhibited cross-resistance to fluconazole (MIC, >=64 ug/ml) and voriconazole (in the absence of established breakpoints, we labeled an isolate resistant to voriconazole if the MIC was >1 ug/ml). Sixteen of the 17 isolates (the exception was C587) exhibited the same pattern of mutations in ERG11; a substitution close to the N terminus of the protein (k128T, Y132H, or Y257H) together with a substitution towards the C terminus of the protein (G405F, G448V, G450E, or G464S).

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [11], [18], [19]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Fluconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain; 5476
• Experiment for Molecule Alteration: Northern blotting analysis
• Experiment for Drug Resistance: NCCLS method M-27A with broth macrodilution techniques assay
• Mechanism Description: The first mechanism involves an altered target site, the cytochrome P-450 lanosterol 14alpha-demethylase, either by overproduction of the enzyme or due to point mutations in its encoding gene (ERG11) leading to amino acid substitutions resulting in decreased affinity of the enzyme for azole derivatives.

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [20]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Molecule Alteration: Missense mutation; p.F72L
• Resistant Drug: Fluconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain; 5476
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Broth macrodilution assay
• Mechanism Description: Amino acid changes in ERG11 may contribute to Candida albicans emerging fluconazole resistance.

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [20]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Molecule Alteration: Missense mutation; p.T132H
• Resistant Drug: Fluconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain; 5476
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Broth macrodilution assay
• Mechanism Description: Amino acid changes in ERG11 may contribute to Candida albicans emerging fluconazole resistance.

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [20]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Molecule Alteration: Missense mutation; p.F126L
• Resistant Drug: Fluconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain; 5476
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Broth macrodilution assay
• Mechanism Description: Amino acid changes in ERG11 may contribute to Candida albicans emerging fluconazole resistance.

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [20]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Molecule Alteration: Missense mutation; p.E266D
• Resistant Drug: Fluconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain; 5476
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Broth macrodilution assay
• Mechanism Description: Amino acid changes in ERG11 may contribute to Candida albicans emerging fluconazole resistance.

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [20]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Molecule Alteration: Missense mutation; p.V437I
• Resistant Drug: Fluconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain; 5476
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Broth macrodilution assay
• Mechanism Description: Amino acid changes in ERG11 may contribute to Candida albicans emerging fluconazole resistance.

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [20]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Molecule Alteration: Missense mutation; p.F449L
• Resistant Drug: Fluconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain; 5476
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Broth macrodilution assay
• Mechanism Description: Amino acid changes in ERG11 may contribute to Candida albicans emerging fluconazole resistance.

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [20]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Molecule Alteration: Missense mutation; p.K143E
• Resistant Drug: Fluconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain; 5476
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Broth macrodilution assay
• Mechanism Description: Amino acid changes in ERG11 may contribute to Candida albicans emerging fluconazole resistance.

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [20]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Molecule Alteration: Missense mutation; p.T229A
• Resistant Drug: Fluconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain; 5476
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Broth macrodilution assay
• Mechanism Description: Amino acid changes in ERG11 may contribute to Candida albicans emerging fluconazole resistance.

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [2]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Fluconazole
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Candida albicans strain; 5476
• Mechanism Description: Overexpression of ERG11 is common in azole-resistant clinical isolates of C. albicans and directly contributes to increased target abundance, ultimately lowering drug susceptibility.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Pleiotropic ABC efflux transporter of multiple drugs CDR1 (CDR1) [17]

• Resistant Disease: Candidosis [ICD-11: 1F23.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Fluconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: South America Candida albicans strain; 5476
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Overexpression of the genes ERG11, CDR1, CDR2, MDR1, and FLU1 has been linked to fluconazole resistance (White et al., 1998) and was investigated as a mechanism of resistance in our clinical isolates by using real-time RT-PCR.

Key Molecule: Multidrug resistance protein CDR2 (CDR2) [17]

• Resistant Disease: Candidosis [ICD-11: 1F23.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Fluconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: South America Candida albicans strain; 5476
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Overexpression of the genes ERG11, CDR1, CDR2, MDR1, and FLU1 has been linked to fluconazole resistance (White et al., 1998) and was investigated as a mechanism of resistance in our clinical isolates by using real-time RT-PCR.

Key Molecule: Major facilitator superfamily multidrug transporter FLU1 (FLU1) [17]

• Resistant Disease: Candidosis [ICD-11: 1F23.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Fluconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: South America Candida albicans strain; 5476
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Overexpression of the genes ERG11, CDR1, CDR2, MDR1, and FLU1 has been linked to fluconazole resistance (White et al., 1998) and was investigated as a mechanism of resistance in our clinical isolates by using real-time RT-PCR.

Key Molecule: Multidrug resistance protein 1 (ABCB1) [17]

• Resistant Disease: Candidosis [ICD-11: 1F23.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Fluconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: South America Candida albicans strain; 5476
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Overexpression of the genes ERG11, CDR1, CDR2, MDR1, and FLU1 has been linked to fluconazole resistance (White et al., 1998) and was investigated as a mechanism of resistance in our clinical isolates by using real-time RT-PCR.

Key Molecule: Multidrug resistance protein 1 (ABCB1) [21]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Fluconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain; 5476
• Experiment for Molecule Alteration: qPCR; TEF3 probe assay
• Experiment for Drug Resistance: Microbroth dilution MIC assay
• Mechanism Description: Failure in accumulating this compound among resistant yeast cells can be related to at least two phenomenona: a significant increase in the level of CDR1 mRNA and a corresponding increase in the level of BENr mRNA. CDR1 and BENr are both multidrug transporter genes, each belonging to distinct classes of transporters.

Key Molecule: Pleiotropic ABC efflux transporter of multiple drugs CDR1 (CDR1) [21]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Fluconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain; 5476
• Experiment for Molecule Alteration: qPCR; TEF3 probe assay
• Experiment for Drug Resistance: Microbroth dilution MIC assay
• Mechanism Description: Failure in accumulating this compound among resistant yeast cells can be related to at least two phenomenona: a significant increase in the level of CDR1 mRNA and a corresponding increase in the level of BENr mRNA. CDR1 and BENr are both multidrug transporter genes, each belonging to distinct classes of transporters.

Key Molecule: Pleiotropic ABC efflux transporter of multiple drugs CDR1 (CDR1) [11], [18], [22]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Fluconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain; 5476
• Experiment for Molecule Alteration: Northern blotting analysis
• Experiment for Drug Resistance: NCCLS method M-27A with broth macrodilution techniques assay
• Mechanism Description: The genes coding for several ABC transporters in C. albicans have been identified, including several CDR genes (19, 26). CDR1 and CDR2 were the first two members of this family identified in C. albicans, and both CDR1 and CDR2 have been described as playing a role in fluconazole resistance.

Key Molecule: Multidrug resistance protein CDR2 (CDR2) [11], [18], [19]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Fluconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain; 5476
• Experiment for Molecule Alteration: Northern blotting analysis
• Experiment for Drug Resistance: NCCLS method M-27A with broth macrodilution techniques assay
• Mechanism Description: The genes coding for several ABC transporters in C. albicans have been identified, including several CDR genes (19, 26). CDR1 and CDR2 were the first two members of this family identified in C. albicans, and both CDR1 and CDR2 have been described as playing a role in fluconazole resistance.

Key Molecule: Multidrug resistance protein 1 (ABCB1) [11], [18], [23]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Fluconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain; 5476
• Experiment for Molecule Alteration: Northern blotting analysis
• Experiment for Drug Resistance: NCCLS method M-27A with broth macrodilution techniques assay
• Mechanism Description: A second major mechanism is through increased efflux of drug, mediated by two types of multidrug efflux pumps, the major facilitators and the ABC transporters. The MDR1 gene encodes a major facilitator implicated in resistance, and its overexpression leads to fluconazole resistance exclusively among azole drugs.

Key Molecule: multidrug resistance regulator 2 (MRR2) [24]

• Resistant Disease: Vulvovaginal candidiasis [ICD-11: 1F23.1]
• Molecule Alteration: Missense mutation; p.T83A
• Resistant Drug: Fluconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans isolates; 5476
• In Vitro Model: Candida albicans ATCC 11006; 5476
• In Vitro Model: Candida parapsilosis ATCC 22019; 5480
• In Vitro Model: Candida krusei ATCC 6258; 4909
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Broth dilution method assay
• Mechanism Description: Efflux pumps including Cdr1 also have been demonstrated as important molecular mechanisms responsible for fluconazole resistance by actively transporting the drug out of the cell.he Mrr2 gene mutation might cause fluconazole resistance through Cdr1 upregulation.

Key Molecule: multidrug resistance regulator 2 (MRR2) [24]

• Resistant Disease: Vulvovaginal candidiasis [ICD-11: 1F23.1]
• Molecule Alteration: Missense mutation; p.T386I
• Resistant Drug: Fluconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans isolates; 5476
• In Vitro Model: Candida albicans ATCC 11006; 5476
• In Vitro Model: Candida parapsilosis ATCC 22019; 5480
• In Vitro Model: Candida krusei ATCC 6258; 4909
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Broth dilution method assay
• Mechanism Description: Efflux pumps including Cdr1 also have been demonstrated as important molecular mechanisms responsible for fluconazole resistance by actively transporting the drug out of the cell.he Mrr2 gene mutation might cause fluconazole resistance through Cdr1 upregulation.

Key Molecule: multidrug resistance regulator 2 (MRR2) [24]

• Resistant Disease: Vulvovaginal candidiasis [ICD-11: 1F23.1]
• Molecule Alteration: Missense mutation; p.S466L
• Resistant Drug: Fluconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans isolates; 5476
• In Vitro Model: Candida albicans ATCC 11006; 5476
• In Vitro Model: Candida parapsilosis ATCC 22019; 5480
• In Vitro Model: Candida krusei ATCC 6258; 4909
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Broth dilution method assay
• Mechanism Description: Efflux pumps including Cdr1 also have been demonstrated as important molecular mechanisms responsible for fluconazole resistance by actively transporting the drug out of the cell.he Mrr2 gene mutation might cause fluconazole resistance through Cdr1 upregulation.

Key Molecule: multidrug resistance regulator 2 (MRR2) [24]

• Resistant Disease: Vulvovaginal candidiasis [ICD-11: 1F23.1]
• Molecule Alteration: Missense mutation; p.H31Y
• Resistant Drug: Fluconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans isolates; 5476
• In Vitro Model: Candida albicans ATCC 11006; 5476
• In Vitro Model: Candida parapsilosis ATCC 22019; 5480
• In Vitro Model: Candida krusei ATCC 6258; 4909
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Broth dilution method assay
• Mechanism Description: Efflux pumps including Cdr1 also have been demonstrated as important molecular mechanisms responsible for fluconazole resistance by actively transporting the drug out of the cell.he Mrr2 gene mutation might cause fluconazole resistance through Cdr1 upregulation.

Key Molecule: Pleiotropic ABC efflux transporter of multiple drugs CDR1 (CDR1) [2]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Fluconazole
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Candida albicans strain; 5476
• Mechanism Description: In C. albicans, overexpression of two homologous ABC transporters, Cdr1 and Cdr2, have been frequently implicated in azole resistance, particularly in patients receiving long-term antifungal therapy.

Key Molecule: Multidrug resistance protein CDR2 (CDR2) [2]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Fluconazole
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Candida albicans strain; 5476
• Mechanism Description: In C. albicans, overexpression of two homologous ABC transporters, Cdr1 and Cdr2, have been frequently implicated in azole resistance, particularly in patients receiving long-term antifungal therapy.

Key Molecule: Multidrug resistance protein 1 (ABCB1) [2]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Fluconazole
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Candida albicans strain; 5476
• Mechanism Description: Although 95 MF transporters are encoded in the C. albicans genome, fluconazole resistance has only been linked to Mdr1 (multidrug resistance 1). Expression of this MF pump is regulated by the transcription factor, Mrr1 (multidrug resistance regulator 1), such that deletion of MRR1 abolishes MDR1 expression and increases susceptibility to fluconazole, whereas activating point mutations in MRR1 increase azole resistance.

Key Molecule: Multidrug resistance regulator 1 (MRR1) [2]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Fluconazole
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Candida albicans strain; 5476
• Mechanism Description: Although 95 MF transporters are encoded in the C. albicans genome, fluconazole resistance has only been linked to Mdr1 (multidrug resistance 1). Expression of this MF pump is regulated by the transcription factor, Mrr1 (multidrug resistance regulator 1), such that deletion of MRR1 abolishes MDR1 expression and increases susceptibility to fluconazole, whereas activating point mutations in MRR1 increase azole resistance.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Heat shock protein HSP 90 (HSP90 ) [2]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Fluconazole
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Candida albicans strain; 5476
• Mechanism Description: The mechanisms through which Hsp90 confers antifungal resistance are complex given its global impact on cellular signaling. A key Hsp90 client that mediates its effects on antifungal drug tolerance and resistance is the calcium-calmodulin activated protein phosphatase calcineurin. Azole treatment activates calcineurin-dependent stress responses in C. albicans, and genetic or pharmacological impairment of the phosphatase renders C. albicans hypersensitive to the azoles. Hsp90 inhibition blocks azole activation of the calcineurin-dependent stress response and phenocopies the effects of calcineurin inhibition, highlighting the interconnectedness between calcineurin and Hsp90 in regulating azole tolerance and resistance.

Key Molecule: Delta(7)-sterol 5(6)-desaturase ERG3 (ERG3) [2]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Molecule Alteration: Missense mutation; p.A168V+p.S191P+p.G261E+p.T329S+p.A353T
• Resistant Drug: Fluconazole
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Candida albicans strain; 5476
• Mechanism Description: A key mechanism through which C. albicans develops resistance to the azoles that is contingent upon stress responses is through alteration of the ergosterol biosynthesis pathway. Loss-of-function mutations in ERG3, which encodes a 5,6-desaturase, block the cellular accumulation of 14-alpha-methyl-3,6-diol, the toxic sterol intermediate that is otherwise produced as a result of Erg11 inhibition by the azoles.106 Alternatively, 14-alpha-methyl fecosterol is incorporated into the fungal cell membrane, allowing for continued growth and replication in the presence of azoles. Azole resistance in C. albicans has been associated with five missense mutations in ERG3 (A168V, S191P, G261E, T329S, and A353T) and two further nonsense mutations (Y325* and Y190*), leading to loss of function.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Phospholipid-translocating ATPase (RTA2) [25]

• Sensitive Disease: Candida albicans infection [ICD-11: 1F23.Y]
• Molecule Alteration: Missense mutation; p.G234S
• Sensitive Drug: Fluconazole
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Calcineurin signaling pathway; Regulation; hsa04310
• In Vitro Model: Candida albicans strain; 5476
• In Vivo Model: Systemic mice candidiasis model; Mus musculus
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Furthermore, we confirmed that G234S mutant enhanced the therapeutic efficacy of fluconazole against systemic candidiasis and significantly increased the accumulation of dihydrosphingosine by decreasing its release.

Key Molecule: Pleiotropic ABC efflux transporter of multiple drugs CDR1 (CDR1) [1]

• Sensitive Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Molecule Alteration: Deletion mutation; Deleteion
• Sensitive Drug: Fluconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain DSY448; 5476
• Experiment for Molecule Alteration: PCR; Southern blotting analysis; Northern blottling analysis
• Experiment for Drug Resistance: Growth differences between the different C. albicans strains assay
• Mechanism Description: The delta cdr1 C. albicans mutant DSY448 was hypersusceptible to the azole derivatives fluconazole, itraconazole, and ketoconazole, thus showing that the ABC transporter Cdr1 can use these compounds as substrates. And this could be attributed to a less efficient fluconazole efflux activity because of the absence of the ABC transporter Cdr1 in the delta cdr1 mutant.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Tethering factor for nuclear proteasome STS1 (STS1) [21]

• Sensitive Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Molecule Alteration: Deletion mutation; Deleteion
• Sensitive Drug: Fluconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Saccharomyces cerevisiae strain; 4932
• Experiment for Molecule Alteration: qPCR; TEF3 probe assay
• Experiment for Drug Resistance: Microbroth dilution MIC assay
• Mechanism Description: The S. cerevisiae sts1 deletion mutant was hypersusceptible to all three azole derivatives used in the study, which is a strong indication that Sts1, a close homolog of Cdr1, is implicated in their transport.

Flucytosine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Fur1 uracil phosphoribosyltransferase (FUR1) [26]

• Resistant Disease: Candida albicans infection [ICD-11: 1F23.Y]
• Molecule Alteration: Missense mutation; p.R101C
• Resistant Drug: Flucytosine
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain; 5476
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: The epidemiological results presented here suggest that the substitution of thymine for cytosine at nucleotide position 301, resulting in a change from arginine to cysteine at amino acid position 101, is likely to be the most important mechanism of 5FC resistance found in C. albicans populations.

Key Molecule: Fur1 uracil phosphoribosyltransferase (FUR1) [5]

• Resistant Disease: Candida auris infection [ICD-11: 1F23.2]
• Molecule Alteration: Missense mutation; p.F211I
• Resistant Drug: Flucytosine
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida auris strain; 498019
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: AFST assay
• Mechanism Description: One isolate displayed resistance to both echinocandins (micafungin, caspofungin, and anidulafungin) and 5-flucytosine; the former was associated with a serine to tyrosine amino acid substitution in the gene FkS1, and the latter was associated with a phenylalanine to isoleucine substitution in the gene FUR1.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [5]

• Resistant Disease: Candida auris infection [ICD-11: 1F23.2]
• Molecule Alteration: Missense mutation; p.Y132F
• Resistant Drug: Flucytosine
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida auris strain; 498019
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: AFST assay
• Mechanism Description: One isolate displayed resistance to both echinocandins (micafungin, caspofungin, and anidulafungin) and 5-flucytosine; the former was associated with a serine to tyrosine amino acid substitution in the gene FkS1, and the latter was associated with a phenylalanine to isoleucine substitution in the gene FUR1.

Fluphenazine

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Pleiotropic ABC efflux transporter of multiple drugs CDR1 (CDR1) [1]

• Sensitive Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Molecule Alteration: Deletion mutation; Deleteion
• Sensitive Drug: Fluphenazine
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain DSY448; 5476
• Experiment for Molecule Alteration: PCR; Southern blotting analysis; Northern blottling analysis
• Experiment for Drug Resistance: Growth differences between the different C. albicans strains assay
• Mechanism Description: The delta cdr1 mutant was also hypersusceptible to other antifungal agents (terbinafine and amorolfine) and to different metabolic inhibitors (cycloheximide, brefeldin A, and fluphenazine).

Gentian violet

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Pleiotropic ABC efflux transporter of multiple drugs CDR1 (CDR1) [1]

• Sensitive Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Molecule Alteration: Deletion mutation; Deleteion
• Sensitive Drug: Gentian violet
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain DSY448; 5476
• Experiment for Molecule Alteration: PCR; Southern blotting analysis; Northern blottling analysis
• Experiment for Drug Resistance: Growth differences between the different C. albicans strains assay
• Mechanism Description: The delta cdr1 mutant was slightly more susceptible than the wild type to nocodazole, cerulenin, and crystal violet but not to amphotericin B, nikkomy- cin Z, flucytosine, or pradimicin.

Isavuconazole

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [4]

• Resistant Disease: Candida auris infection [ICD-11: 1F23.2]
• Molecule Alteration: Missense mutation; p.Y132F
• Resistant Drug: Isavuconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida auris strain; 498019
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: CLSI broth microdilution method assay
• Mechanism Description: Overall, among 45% (n = 20) of isolates that had Y132F and k143R substitutions, 16 showed cross-resistance to one or more azoles namely voriconazole, isavuconazole and posaconazole and four were pan-azole resistant.

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [4]

• Resistant Disease: Candida auris infection [ICD-11: 1F23.2]
• Molecule Alteration: Missense mutation; p.K143R
• Resistant Drug: Isavuconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida auris strain; 498019
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: CLSI broth microdilution method assay
• Mechanism Description: Overall, among 45% (n = 20) of isolates that had Y132F and k143R substitutions, 16 showed cross-resistance to one or more azoles namely voriconazole, isavuconazole and posaconazole and four were pan-azole resistant.

Itraconazole

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [14]

• Resistant Disease: Candida albicans infection [ICD-11: 1F23.Y]
• Molecule Alteration: Missense mutation; p.Y132F+p.Y205E+p.Y257H+p.D116E+p.K143Q
• Resistant Drug: Itraconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain; 5476
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: M27-A2 broth dilution method assay
• Mechanism Description: We observed that substitutions A114S, Y132H, Y132F, k143R, Y257H, and a new k143Q substitution contributed to significant increases ( fourfold) in fluconazole and voriconazole resistance; changes in itraconazole resistance were not significant (twofold).

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [14]

• Resistant Disease: Candida albicans infection [ICD-11: 1F23.Y]
• Molecule Alteration: Missense mutation; p.Y132F+p.Y205E+p.V437I+p.D116E+p.K143Q
• Resistant Drug: Itraconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain; 5476
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: M27-A2 broth dilution method assay
• Mechanism Description: We observed that substitutions A114S, Y132H, Y132F, k143R, Y257H, and a new k143Q substitution contributed to significant increases ( fourfold) in fluconazole and voriconazole resistance; changes in itraconazole resistance were not significant (twofold).

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [14]

• Resistant Disease: Candida albicans infection [ICD-11: 1F23.Y]
• Molecule Alteration: Missense mutation; p.A114S+p.Y205E+p.Y257H+p.V437I
• Resistant Drug: Itraconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain; 5476
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: M27-A2 broth dilution method assay
• Mechanism Description: We observed that substitutions A114S, Y132H, Y132F, k143R, Y257H, and a new k143Q substitution contributed to significant increases ( fourfold) in fluconazole and voriconazole resistance; changes in itraconazole resistance were not significant (twofold).

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [14]

• Resistant Disease: Candida albicans infection [ICD-11: 1F23.Y]
• Molecule Alteration: Missense mutation; p.Y205E+p.V437I+p.Y132H+p.G472R
• Resistant Drug: Itraconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain; 5476
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: M27-A2 broth dilution method assay
• Mechanism Description: We observed that substitutions A114S, Y132H, Y132F, k143R, Y257H, and a new k143Q substitution contributed to significant increases ( fourfold) in fluconazole and voriconazole resistance; changes in itraconazole resistance were not significant (twofold).

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [12]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Molecule Alteration: Missense mutation; p.Y132H
• Resistant Drug: Itraconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain YkkB-13; 5476
• Experiment for Molecule Alteration: Gene Sequencing asay; RFLP assay; Immunoblotting assay
• Experiment for Drug Resistance: Disk diffusion assays; Microbroth dilution MIC assay
• Mechanism Description: Site-directed mutagenesis of a wild-type CYP51A1 gene was performed to estimate the effect of each of these mutations on resistance to azole derivatives. Each single mutation, with the exception of G129A, had a measurable effect on the affinity of the target enzyme for specific azole derivatives.

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [12]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Molecule Alteration: Missense mutation; p.G464S
• Resistant Drug: Itraconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain YkkB-13; 5476
• Experiment for Molecule Alteration: Gene Sequencing asay; RFLP assay; Immunoblotting assay
• Experiment for Drug Resistance: Disk diffusion assays; Microbroth dilution MIC assay
• Mechanism Description: Site-directed mutagenesis of a wild-type CYP51A1 gene was performed to estimate the effect of each of these mutations on resistance to azole derivatives. Each single mutation, with the exception of G129A, had a measurable effect on the affinity of the target enzyme for specific azole derivatives.

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [12]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Molecule Alteration: Missense mutation; p.R467K
• Resistant Drug: Itraconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain YkkB-13; 5476
• Experiment for Molecule Alteration: Gene Sequencing asay; RFLP assay; Immunoblotting assay
• Experiment for Drug Resistance: Disk diffusion assays; Microbroth dilution MIC assay
• Mechanism Description: Site-directed mutagenesis of a wild-type CYP51A1 gene was performed to estimate the effect of each of these mutations on resistance to azole derivatives. Each single mutation, with the exception of G129A, had a measurable effect on the affinity of the target enzyme for specific azole derivatives.

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [12]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Molecule Alteration: Missense mutation; p.S405F+p.Y132H
• Resistant Drug: Itraconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain YkkB-13; 5476
• Experiment for Molecule Alteration: Gene Sequencing asay; RFLP assay; Immunoblotting assay
• Experiment for Drug Resistance: Disk diffusion assays; Microbroth dilution MIC assay
• Mechanism Description: Site-directed mutagenesis of a wild-type CYP51A1 gene was performed to estimate the effect of each of these mutations on resistance to azole derivatives. Each single mutation, with the exception of G129A, had a measurable effect on the affinity of the target enzyme for specific azole derivatives.

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [12]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Molecule Alteration: Missense mutation; p.G464S+p.Y132H
• Resistant Drug: Itraconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain YkkB-13; 5476
• Experiment for Molecule Alteration: Gene Sequencing asay; RFLP assay; Immunoblotting assay
• Experiment for Drug Resistance: Disk diffusion assays; Microbroth dilution MIC assay
• Mechanism Description: Site-directed mutagenesis of a wild-type CYP51A1 gene was performed to estimate the effect of each of these mutations on resistance to azole derivatives. Each single mutation, with the exception of G129A, had a measurable effect on the affinity of the target enzyme for specific azole derivatives.

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [12]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Molecule Alteration: Missense mutation; p.G464S+p.R467K
• Resistant Drug: Itraconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain YkkB-13; 5476
• Experiment for Molecule Alteration: Gene Sequencing asay; RFLP assay; Immunoblotting assay
• Experiment for Drug Resistance: Disk diffusion assays; Microbroth dilution MIC assay
• Mechanism Description: Site-directed mutagenesis of a wild-type CYP51A1 gene was performed to estimate the effect of each of these mutations on resistance to azole derivatives. Each single mutation, with the exception of G129A, had a measurable effect on the affinity of the target enzyme for specific azole derivatives.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Pleiotropic ABC efflux transporter of multiple drugs CDR1 (CDR1) [1]

• Sensitive Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Molecule Alteration: Deletion mutation; Deleteion
• Sensitive Drug: Itraconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain DSY448; 5476
• Experiment for Molecule Alteration: PCR; Southern blotting analysis; Northern blottling analysis
• Experiment for Drug Resistance: Growth differences between the different C. albicans strains assay
• Mechanism Description: The delta cdr1 C. albicans mutant DSY448 was hypersusceptible to the azole derivatives fluconazole, itraconazole, and ketoconazole, thus showing that the ABC transporter Cdr1 can use these compounds as substrates. And this could be attributed to a less efficient fluconazole efflux activity because of the absence of the ABC transporter Cdr1 in the delta cdr1 mutant.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Tethering factor for nuclear proteasome STS1 (STS1) [21]

• Sensitive Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Molecule Alteration: Deletion mutation; Deleteion
• Sensitive Drug: Itraconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Saccharomyces cerevisiae strain; 4932
• Experiment for Molecule Alteration: qPCR; TEF3 probe assay
• Experiment for Drug Resistance: Microbroth dilution MIC assay
• Mechanism Description: The S. cerevisiae sts1 deletion mutant was hypersusceptible to all three azole derivatives used in the study, which is a strong indication that Sts1, a close homolog of Cdr1, is implicated in their transport.

Ketoconazole

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [12]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Molecule Alteration: Missense mutation; p.Y132H
• Resistant Drug: Ketoconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain YkkB-13; 5476
• Experiment for Molecule Alteration: Gene Sequencing asay; RFLP assay; Immunoblotting assay
• Experiment for Drug Resistance: Disk diffusion assays; Microbroth dilution MIC assay
• Mechanism Description: Site-directed mutagenesis of a wild-type CYP51A1 gene was performed to estimate the effect of each of these mutations on resistance to azole derivatives. Each single mutation, with the exception of G129A, had a measurable effect on the affinity of the target enzyme for specific azole derivatives.

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [12]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Molecule Alteration: Missense mutation; p.S405F+p.Y132H
• Resistant Drug: Ketoconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain YkkB-13; 5476
• Experiment for Molecule Alteration: Gene Sequencing asay; RFLP assay; Immunoblotting assay
• Experiment for Drug Resistance: Disk diffusion assays; Microbroth dilution MIC assay
• Mechanism Description: Site-directed mutagenesis of a wild-type CYP51A1 gene was performed to estimate the effect of each of these mutations on resistance to azole derivatives. Each single mutation, with the exception of G129A, had a measurable effect on the affinity of the target enzyme for specific azole derivatives.

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [12]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Molecule Alteration: Missense mutation; p.G464S+p.Y132H
• Resistant Drug: Ketoconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain YkkB-13; 5476
• Experiment for Molecule Alteration: Gene Sequencing asay; RFLP assay; Immunoblotting assay
• Experiment for Drug Resistance: Disk diffusion assays; Microbroth dilution MIC assay
• Mechanism Description: Site-directed mutagenesis of a wild-type CYP51A1 gene was performed to estimate the effect of each of these mutations on resistance to azole derivatives. Each single mutation, with the exception of G129A, had a measurable effect on the affinity of the target enzyme for specific azole derivatives.

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [12]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Molecule Alteration: Missense mutation; p.G464S+p.R467K
• Resistant Drug: Ketoconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain YkkB-13; 5476
• Experiment for Molecule Alteration: Gene Sequencing asay; RFLP assay; Immunoblotting assay
• Experiment for Drug Resistance: Disk diffusion assays; Microbroth dilution MIC assay
• Mechanism Description: Site-directed mutagenesis of a wild-type CYP51A1 gene was performed to estimate the effect of each of these mutations on resistance to azole derivatives. Each single mutation, with the exception of G129A, had a measurable effect on the affinity of the target enzyme for specific azole derivatives.

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [12]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Molecule Alteration: Missense mutation; p.G464S+p.G129A
• Resistant Drug: Ketoconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain YkkB-13; 5476
• Experiment for Molecule Alteration: Gene Sequencing asay; RFLP assay; Immunoblotting assay
• Experiment for Drug Resistance: Disk diffusion assays; Microbroth dilution MIC assay
• Mechanism Description: Site-directed mutagenesis of a wild-type CYP51A1 gene was performed to estimate the effect of each of these mutations on resistance to azole derivatives. Each single mutation, with the exception of G129A, had a measurable effect on the affinity of the target enzyme for specific azole derivatives.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Pleiotropic ABC efflux transporter of multiple drugs CDR1 (CDR1) [1]

• Sensitive Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Molecule Alteration: Deletion mutation; Deleteion
• Sensitive Drug: Ketoconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain DSY448; 5476
• Experiment for Molecule Alteration: PCR; Southern blotting analysis; Northern blottling analysis
• Experiment for Drug Resistance: Growth differences between the different C. albicans strains assay
• Mechanism Description: The delta cdr1 C. albicans mutant DSY448 was hypersusceptible to the azole derivatives fluconazole, itraconazole, and ketoconazole, thus showing that the ABC transporter Cdr1 can use these compounds as substrates. And this could be attributed to a less efficient fluconazole efflux activity because of the absence of the ABC transporter Cdr1 in the delta cdr1 mutant.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Tethering factor for nuclear proteasome STS1 (STS1) [21]

• Sensitive Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Molecule Alteration: Deletion mutation; Deleteion
• Sensitive Drug: Ketoconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Saccharomyces cerevisiae strain; 4932
• Experiment for Molecule Alteration: qPCR; TEF3 probe assay
• Experiment for Drug Resistance: Microbroth dilution MIC assay
• Mechanism Description: The S. cerevisiae sts1 deletion mutant was hypersusceptible to all three azole derivatives used in the study, which is a strong indication that Sts1, a close homolog of Cdr1, is implicated in their transport.

Micafungin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: D-glucan-1,3-beta--UDP glucosyltransferase (FKS1) [3]

• Resistant Disease: Candida auris infection [ICD-11: 1F23.2]
• Molecule Alteration: Missense mutation; p.S639P
• Resistant Drug: Micafungin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida auris strain; 498019
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: AFST assay
• Mechanism Description: Sequencing of FkS revealed that 4 isolates contain the amino acid substitution S639P and those isolates exhibit the highest MICs to echinocandins (micafungin, caspofungin, and anidulafungin, CD101).

Key Molecule: D-glucan-1,3-beta--UDP glucosyltransferase (FKS1) [4]

• Resistant Disease: Candida auris infection [ICD-11: 1F23.2]
• Molecule Alteration: Missense mutation; p.S639F
• Resistant Drug: Micafungin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida auris strain; 498019
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: CLSI broth microdilution method assay
• Mechanism Description: Echinocandin (micafungin, caspofungin, and anidulafungin) resistance was linked to a novel mutation S639F in FkS1 hot spot region I.

Key Molecule: D-glucan-1,3-beta--UDP glucosyltransferase (FKS1) [5]

• Resistant Disease: Candida auris infection [ICD-11: 1F23.2]
• Molecule Alteration: Missense mutation; p.S652Y
• Resistant Drug: Micafungin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida auris strain; 498019
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: AFST assay
• Mechanism Description: One isolate displayed resistance to both echinocandins (micafungin, caspofungin, and anidulafungin) and 5-flucytosine; the former was associated with a serine to tyrosine amino acid substitution in the gene FkS1, and the latter was associated with a phenylalanine to isoleucine substitution in the gene FUR1.

Key Molecule: D-glucan-1,3-beta--UDP glucosyltransferase (FKS1) [6]

• Resistant Disease: Candida glabrata infection [ICD-11: 1F23.3]
• Molecule Alteration: Missense mutation; p.D632G (c.A1895G)
• Resistant Drug: Micafungin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida glabrata strain; 5478
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: NCCLS method M-27A with broth macrodilution techniques assay
• Mechanism Description: Fks1p and Fks2p amino acid substitutions confer reduced echinocandin susceptibility in C. glabrata.

Key Molecule: D-glucan-1,3-beta--UDP glucosyltransferase (FKS1) [6]

• Resistant Disease: Candida glabrata infection [ICD-11: 1F23.3]
• Molecule Alteration: Missense mutation; p.D632E (c.T1896G)
• Resistant Drug: Micafungin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida glabrata strain; 5478
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: NCCLS method M-27A with broth macrodilution techniques assay
• Mechanism Description: Recently, three reports showed that amino acid substitutions in Fks1p (D632E) and Fks2p (F659V) are responsible for clinical echinocandin resistance in C. glabrata.

Key Molecule: D-glucan-1,3-beta--UDP glucosyltransferase (FKS1) [6]

• Resistant Disease: Candida glabrata infection [ICD-11: 1F23.3]
• Molecule Alteration: Missense mutation; p.D632Y (c.G1894T)
• Resistant Drug: Micafungin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida glabrata strain; 5478
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: NCCLS method M-27A with broth macrodilution techniques assay
• Mechanism Description: Fks1p and Fks2p amino acid substitutions confer reduced echinocandin susceptibility in C. glabrata.

Key Molecule: D-glucan-1,3-beta--UDP glucosyltransferase (FKS1) [6]

• Resistant Disease: Candida glabrata infection [ICD-11: 1F23.3]
• Molecule Alteration: Missense mutation; p.F625S (c.T1874C)
• Resistant Drug: Micafungin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida glabrata strain; 5478
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: NCCLS method M-27A with broth macrodilution techniques assay
• Mechanism Description: Fks1p and Fks2p amino acid substitutions confer reduced echinocandin susceptibility in C. glabrata.

Key Molecule: D-glucan-1,3-beta--UDP glucosyltransferase (FKS1) [6]

• Resistant Disease: Candida glabrata infection [ICD-11: 1F23.3]
• Molecule Alteration: Missense mutation; p.S629P (c.T1885C)
• Resistant Drug: Micafungin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida glabrata strain; 5478
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: NCCLS method M-27A with broth macrodilution techniques assay
• Mechanism Description: Fks1p and Fks2p amino acid substitutions confer reduced echinocandin susceptibility in C. glabrata.

Key Molecule: D-glucan-1,3-beta--UDP glucosyltransferase (FKS1) [6]

• Resistant Disease: Candida glabrata infection [ICD-11: 1F23.3]
• Molecule Alteration: Missense mutation; p.F659V (c.T1975G)
• Resistant Drug: Micafungin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida glabrata strain; 5478
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: NCCLS method M-27A with broth macrodilution techniques assay
• Mechanism Description: Recently, three reports showed that amino acid substitutions in Fks1p (D632E) and Fks2p (F659V) are responsible for clinical echinocandin resistance in C. glabrata.

Key Molecule: D-glucan-1,3-beta--UDP glucosyltransferase (FKS1) [6]

• Resistant Disease: Candida glabrata infection [ICD-11: 1F23.3]
• Molecule Alteration: Missense mutation; p.F659S (c.T1976C)
• Resistant Drug: Micafungin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida glabrata strain; 5478
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: NCCLS method M-27A with broth macrodilution techniques assay
• Mechanism Description: Fks1p and Fks2p amino acid substitutions confer reduced echinocandin susceptibility in C. glabrata.

Key Molecule: D-glucan-1,3-beta--UDP glucosyltransferase (FKS1) [6]

• Resistant Disease: Candida glabrata infection [ICD-11: 1F23.3]
• Molecule Alteration: Frameshift mutation; p.F659del (c.1974-CTT-1976)
• Resistant Drug: Micafungin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida glabrata strain; 5478
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: NCCLS method M-27A with broth macrodilution techniques assay
• Mechanism Description: Fks1p and Fks2p amino acid substitutions confer reduced echinocandin susceptibility in C. glabrata.

Key Molecule: D-glucan-1,3-beta--UDP glucosyltransferase (FKS1) [6]

• Resistant Disease: Candida glabrata infection [ICD-11: 1F23.3]
• Molecule Alteration: Nonsense mutation; p.R1377STOP (c.A4129T)
• Resistant Drug: Micafungin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida glabrata strain; 5478
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: NCCLS method M-27A with broth macrodilution techniques assay
• Mechanism Description: Fks1p and Fks2p amino acid substitutions confer reduced echinocandin susceptibility in C. glabrata.

Key Molecule: D-glucan-1,3-beta--UDP glucosyltransferase (FKS1) [7]

• Resistant Disease: Candida krusei infection [ICD-11: 1F23.4]
• Molecule Alteration: Missense mutation; p.F655C
• Resistant Drug: Micafungin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida krusei strain; 4909
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Broth macrodilution assay
• Mechanism Description: A Candida krusei strain from a patient with acute myelogenous leukemia that displayed reduced susceptibility to echinocandin drugs contained a heterozygous mutation, T2080k, in FkS1. The resulting Phe655-Cys substitution altered the sensitivity of glucan synthase to echinocandin drugs, consistent with a common mechanism for echinocandin resistance in Candida spp.

Key Molecule: D-glucan-1,3-beta--UDP glucosyltransferase (FKS1) [8]

• Resistant Disease: Invasive candidiasis [ICD-11: 1F23.5]
• Molecule Alteration: Missense mutation; p.P660A
• Resistant Drug: Micafungin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida parapsilosis strain; 5480
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: M27-A2 broth dilution method assay
• Mechanism Description: Overall, these data firmly indicate that a naturally occurring P660A substitution in Fks1p from the C. parapsilosis group accounts for the reduced susceptibility phenotype.

Posaconazole

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [4]

• Resistant Disease: Candida auris infection [ICD-11: 1F23.2]
• Molecule Alteration: Missense mutation; p.Y132F
• Resistant Drug: Posaconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida auris strain; 498019
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: CLSI broth microdilution method assay
• Mechanism Description: Overall, among 45% (n = 20) of isolates that had Y132F and k143R substitutions, 16 showed cross-resistance to one or more azoles namely voriconazole, isavuconazole and posaconazole and four were pan-azole resistant.

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [4]

• Resistant Disease: Candida auris infection [ICD-11: 1F23.2]
• Molecule Alteration: Missense mutation; p.K143R
• Resistant Drug: Posaconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida auris strain; 498019
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: CLSI broth microdilution method assay
• Mechanism Description: Overall, among 45% (n = 20) of isolates that had Y132F and k143R substitutions, 16 showed cross-resistance to one or more azoles namely voriconazole, isavuconazole and posaconazole and four were pan-azole resistant.

Rezafungin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: D-glucan-1,3-beta--UDP glucosyltransferase (FKS1) [3]

• Resistant Disease: Candida auris infection [ICD-11: 1F23.2]
• Molecule Alteration: Missense mutation; p.S639P
• Resistant Drug: Rezafungin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida auris strain; 498019
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Broth microdilution assay
• Mechanism Description: Sequencing of FkS revealed that 4 isolates contain the amino acid substitution S639P and those isolates exhibit the highest MICs to echinocandins (micafungin, caspofungin, and anidulafungin, CD101).

Terbinafine

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Pleiotropic ABC efflux transporter of multiple drugs CDR1 (CDR1) [1]

• Sensitive Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Molecule Alteration: Deletion mutation; Deleteion
• Sensitive Drug: Terbinafine
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain DSY448; 5476
• Experiment for Molecule Alteration: PCR; Southern blotting analysis; Northern blottling analysis
• Experiment for Drug Resistance: Growth differences between the different C. albicans strains assay
• Mechanism Description: The delta cdr1 mutant was also hypersusceptible to other antifungal agents (terbinafine and amorolfine) and to different metabolic inhibitors (cycloheximide, brefeldin A, and fluphenazine).

Voriconazole

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [4]

• Resistant Disease: Candida auris infection [ICD-11: 1F23.2]
• Molecule Alteration: Missense mutation; p.Y132F
• Resistant Drug: Voriconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida auris strain; 498019
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: CLSI broth microdilution method assay
• Mechanism Description: Overall, among 45% (n = 20) of isolates that had Y132F and k143R substitutions, 16 showed cross-resistance to one or more azoles namely voriconazole, isavuconazole and posaconazole and four were pan-azole resistant.

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [4]

• Resistant Disease: Candida auris infection [ICD-11: 1F23.2]
• Molecule Alteration: Missense mutation; p.K143R
• Resistant Drug: Voriconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida auris strain; 498019
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: CLSI broth microdilution method assay
• Mechanism Description: Overall, among 45% (n = 20) of isolates that had Y132F and k143R substitutions, 16 showed cross-resistance to one or more azoles namely voriconazole, isavuconazole and posaconazole and four were pan-azole resistant.

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [11]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Molecule Alteration: Missense mutation; p.Y132H+p.G450E
• Resistant Drug: Voriconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain C572; 5476
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Broth microdilution assay
• Mechanism Description: Seventeen of the 38 isolates analyzed exhibited cross-resistance to fluconazole (MIC, >=64 ug/ml) and voriconazole (in the absence of established breakpoints, we labeled an isolate resistant to voriconazole if the MIC was >1 ug/ml). Sixteen of the 17 isolates (the exception was C587) exhibited the same pattern of mutations in ERG11; a substitution close to the N terminus of the protein (k128T, Y132H, or Y257H) together with a substitution towards the C terminus of the protein (G405F, G448V, G450E, or G464S).

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [11]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Molecule Alteration: Missense mutation; p.G450E+p.G464S
• Resistant Drug: Voriconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain C530; 5476
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Broth microdilution assay
• Mechanism Description: Seventeen of the 38 isolates analyzed exhibited cross-resistance to fluconazole (MIC, >=64 ug/ml) and voriconazole (in the absence of established breakpoints, we labeled an isolate resistant to voriconazole if the MIC was >1 ug/ml). Sixteen of the 17 isolates (the exception was C587) exhibited the same pattern of mutations in ERG11; a substitution close to the N terminus of the protein (k128T, Y132H, or Y257H) together with a substitution towards the C terminus of the protein (G405F, G448V, G450E, or G464S).

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [11]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Molecule Alteration: Missense mutation; p.Y132H+p.G448V
• Resistant Drug: Voriconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain C535; 5476
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Broth microdilution assay
• Mechanism Description: Seventeen of the 38 isolates analyzed exhibited cross-resistance to fluconazole (MIC, >=64 ug/ml) and voriconazole (in the absence of established breakpoints, we labeled an isolate resistant to voriconazole if the MIC was >1 ug/ml). Sixteen of the 17 isolates (the exception was C587) exhibited the same pattern of mutations in ERG11; a substitution close to the N terminus of the protein (k128T, Y132H, or Y257H) together with a substitution towards the C terminus of the protein (G405F, G448V, G450E, or G464S).

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [11]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Molecule Alteration: Missense mutation; p.S405F
• Resistant Drug: Voriconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain C470; 5476
• In Vitro Model: Candida albicans strain C478; 5476
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Broth microdilution assay
• Mechanism Description: Seventeen of the 38 isolates analyzed exhibited cross-resistance to fluconazole (MIC, >=64 ug/ml) and voriconazole (in the absence of established breakpoints, we labeled an isolate resistant to voriconazole if the MIC was >1 ug/ml). Sixteen of the 17 isolates (the exception was C587) exhibited the same pattern of mutations in ERG11; a substitution close to the N terminus of the protein (k128T, Y132H, or Y257H) together with a substitution towards the C terminus of the protein (G405F, G448V, G450E, or G464S).

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [11]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Molecule Alteration: Missense mutation; p.K128T+p.V452A
• Resistant Drug: Voriconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain C497; 5476
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Broth microdilution assay
• Mechanism Description: Seventeen of the 38 isolates analyzed exhibited cross-resistance to fluconazole (MIC, >=64 ug/ml) and voriconazole (in the absence of established breakpoints, we labeled an isolate resistant to voriconazole if the MIC was >1 ug/ml). Sixteen of the 17 isolates (the exception was C587) exhibited the same pattern of mutations in ERG11; a substitution close to the N terminus of the protein (k128T, Y132H, or Y257H) together with a substitution towards the C terminus of the protein (G405F, G448V, G450E, or G464S).

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [11]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Molecule Alteration: Missense mutation; p.Y132H+p.S405F
• Resistant Drug: Voriconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain C600; 5476
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Broth microdilution assay
• Mechanism Description: Seventeen of the 38 isolates analyzed exhibited cross-resistance to fluconazole (MIC, >=64 ug/ml) and voriconazole (in the absence of established breakpoints, we labeled an isolate resistant to voriconazole if the MIC was >1 ug/ml). Sixteen of the 17 isolates (the exception was C587) exhibited the same pattern of mutations in ERG11; a substitution close to the N terminus of the protein (k128T, Y132H, or Y257H) together with a substitution towards the C terminus of the protein (G405F, G448V, G450E, or G464S).

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [11]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Molecule Alteration: Missense mutation; p.G464S
• Resistant Drug: Voriconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain C587; 5476
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Broth microdilution assay
• Mechanism Description: Seventeen of the 38 isolates analyzed exhibited cross-resistance to fluconazole (MIC, >=64 ug/ml) and voriconazole (in the absence of established breakpoints, we labeled an isolate resistant to voriconazole if the MIC was >1 ug/ml). Sixteen of the 17 isolates (the exception was C587) exhibited the same pattern of mutations in ERG11; a substitution close to the N terminus of the protein (k128T, Y132H, or Y257H) together with a substitution towards the C terminus of the protein (G405F, G448V, G450E, or G464S).

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [11]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Molecule Alteration: Missense mutation; p.G464S+p.K128T+p.R467I
• Resistant Drug: Voriconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain C477; 5476
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Broth microdilution assay
• Mechanism Description: Seventeen of the 38 isolates analyzed exhibited cross-resistance to fluconazole (MIC, >=64 ug/ml) and voriconazole (in the absence of established breakpoints, we labeled an isolate resistant to voriconazole if the MIC was >1 ug/ml). Sixteen of the 17 isolates (the exception was C587) exhibited the same pattern of mutations in ERG11; a substitution close to the N terminus of the protein (k128T, Y132H, or Y257H) together with a substitution towards the C terminus of the protein (G405F, G448V, G450E, or G464S).

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [11]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Molecule Alteration: Missense mutation; p.Y257H+p.G464S
• Resistant Drug: Voriconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain C438; 5476
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Broth microdilution assay
• Mechanism Description: Seventeen of the 38 isolates analyzed exhibited cross-resistance to fluconazole (MIC, >=64 ug/ml) and voriconazole (in the absence of established breakpoints, we labeled an isolate resistant to voriconazole if the MIC was >1 ug/ml). Sixteen of the 17 isolates (the exception was C587) exhibited the same pattern of mutations in ERG11; a substitution close to the N terminus of the protein (k128T, Y132H, or Y257H) together with a substitution towards the C terminus of the protein (G405F, G448V, G450E, or G464S).

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [11]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Molecule Alteration: Missense mutation; p.A61V+p.Y257H+p.G464S+p.G307S
• Resistant Drug: Voriconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain C440; 5476
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Broth microdilution assay
• Mechanism Description: Seventeen of the 38 isolates analyzed exhibited cross-resistance to fluconazole (MIC, >=64 ug/ml) and voriconazole (in the absence of established breakpoints, we labeled an isolate resistant to voriconazole if the MIC was >1 ug/ml). Sixteen of the 17 isolates (the exception was C587) exhibited the same pattern of mutations in ERG11; a substitution close to the N terminus of the protein (k128T, Y132H, or Y257H) together with a substitution towards the C terminus of the protein (G405F, G448V, G450E, or G464S).

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [11]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Molecule Alteration: Missense mutation; p.Y257H+p.G464S+p.G307S
• Resistant Drug: Voriconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain C439; 5476
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Broth microdilution assay
• Mechanism Description: Seventeen of the 38 isolates analyzed exhibited cross-resistance to fluconazole (MIC, >=64 ug/ml) and voriconazole (in the absence of established breakpoints, we labeled an isolate resistant to voriconazole if the MIC was >1 ug/ml). Sixteen of the 17 isolates (the exception was C587) exhibited the same pattern of mutations in ERG11; a substitution close to the N terminus of the protein (k128T, Y132H, or Y257H) together with a substitution towards the C terminus of the protein (G405F, G448V, G450E, or G464S).

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [11]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Molecule Alteration: Missense mutation; p.K143R
• Resistant Drug: Voriconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain C441; 5476
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Broth microdilution assay
• Mechanism Description: Seventeen of the 38 isolates analyzed exhibited cross-resistance to fluconazole (MIC, >=64 ug/ml) and voriconazole (in the absence of established breakpoints, we labeled an isolate resistant to voriconazole if the MIC was >1 ug/ml). Sixteen of the 17 isolates (the exception was C587) exhibited the same pattern of mutations in ERG11; a substitution close to the N terminus of the protein (k128T, Y132H, or Y257H) together with a substitution towards the C terminus of the protein (G405F, G448V, G450E, or G464S).

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [11]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Molecule Alteration: Missense mutation; p.Y257H+p.Y132H+p.E266D
• Resistant Drug: Voriconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain C489; 5476
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Broth microdilution assay
• Mechanism Description: Seventeen of the 38 isolates analyzed exhibited cross-resistance to fluconazole (MIC, >=64 ug/ml) and voriconazole (in the absence of established breakpoints, we labeled an isolate resistant to voriconazole if the MIC was >1 ug/ml). Sixteen of the 17 isolates (the exception was C587) exhibited the same pattern of mutations in ERG11; a substitution close to the N terminus of the protein (k128T, Y132H, or Y257H) together with a substitution towards the C terminus of the protein (G405F, G448V, G450E, or G464S).

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [11]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Molecule Alteration: Missense mutation; p.Y132H+p.G464S+p.H283R
• Resistant Drug: Voriconazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain C507; 5476
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Broth microdilution assay
• Mechanism Description: Seventeen of the 38 isolates analyzed exhibited cross-resistance to fluconazole (MIC, >=64 ug/ml) and voriconazole (in the absence of established breakpoints, we labeled an isolate resistant to voriconazole if the MIC was >1 ug/ml). Sixteen of the 17 isolates (the exception was C587) exhibited the same pattern of mutations in ERG11; a substitution close to the N terminus of the protein (k128T, Y132H, or Y257H) together with a substitution towards the C terminus of the protein (G405F, G448V, G450E, or G464S).

Investigative Drug(s) 5 drug(s) in total

Brefeldin A

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Pleiotropic ABC efflux transporter of multiple drugs CDR1 (CDR1) [1]

• Sensitive Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Molecule Alteration: Deletion mutation; Deleteion
• Sensitive Drug: Brefeldin A
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain DSY448; 5476
• Experiment for Molecule Alteration: PCR; Southern blotting analysis; Northern blottling analysis
• Experiment for Drug Resistance: Growth differences between the different C. albicans strains assay
• Mechanism Description: The delta cdr1 mutant was also hypersusceptible to other antifungal agents (terbinafine and amorolfine) and to different metabolic inhibitors (cycloheximide, brefeldin A, and fluphenazine).

Cerulenin

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Pleiotropic ABC efflux transporter of multiple drugs CDR1 (CDR1) [1]

• Sensitive Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Molecule Alteration: Deletion mutation; Deleteion
• Sensitive Drug: Cerulenin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain DSY448; 5476
• Experiment for Molecule Alteration: PCR; Southern blotting analysis; Northern blottling analysis
• Experiment for Drug Resistance: Growth differences between the different C. albicans strains assay
• Mechanism Description: The delta cdr1 mutant was slightly more susceptible than the wild type to nocodazole, cerulenin, and crystal violet but not to amphotericin B, nikkomy- cin Z, flucytosine, or pradimicin.

Key Molecule: Pleiotropic ABC efflux transporter of multiple drugs CDR /Multidrug resistance protein 1 (CDR1/ABCB1) [1]

• Sensitive Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Molecule Alteration: Deletion mutation; Deleteion
• Sensitive Drug: Cerulenin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida tropicalis strain DSY468; 5482
• Experiment for Molecule Alteration: PCR; Southern blotting analysis; Northern blottling analysis
• Experiment for Drug Resistance: Growth differences between the different C. albicans strains assay
• Mechanism Description: The double delta cdr1 and delta ben mutant DSY468 showed increased growth inhibition in plates containing cyclo-heximide and cerulenin compared with the growth of strain CAF2-1 and of the delta ben mutant DSY465. A slight increase in the level of inhibition of DSY468 compared with that of the delta cdr1 mutant DSY448 was observed with cycloheximide, whereas this effect was more severe with cerulenin.

Cycloheximide

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Pleiotropic ABC efflux transporter of multiple drugs CDR1 (CDR1) [1]

• Sensitive Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Molecule Alteration: Deletion mutation; Deleteion
• Sensitive Drug: Cycloheximide
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain DSY448; 5476
• Experiment for Molecule Alteration: PCR; Southern blotting analysis; Northern blottling analysis
• Experiment for Drug Resistance: Growth differences between the different C. albicans strains assay
• Mechanism Description: The delta cdr1 mutant was also hypersusceptible to other antifungal agents (terbinafine and amorolfine) and to different metabolic inhibitors (cycloheximide, brefeldin A, and fluphenazine).

Key Molecule: Pleiotropic ABC efflux transporter of multiple drugs CDR /Multidrug resistance protein 1 (CDR1/ABCB1) [1]

• Sensitive Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Molecule Alteration: Deletion mutation; Deleteion
• Sensitive Drug: Cycloheximide
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida tropicalis strain DSY468; 5482
• Experiment for Molecule Alteration: PCR; Southern blotting analysis; Northern blottling analysis
• Experiment for Drug Resistance: Growth differences between the different C. albicans strains assay
• Mechanism Description: The double delta cdr1 and delta ben mutant DSY468 showed increased growth inhibition in plates containing cyclo-heximide and cerulenin compared with the growth of strain CAF2-1 and of the delta ben mutant DSY465. A slight increase in the level of inhibition of DSY468 compared with that of the delta cdr1 mutant DSY448 was observed with cycloheximide, whereas this effect was more severe with cerulenin.

Echinocandins

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: D-glucan-1,3-beta--UDP glucosyltransferase (FKS1) [2]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Molecule Alteration: Mutation; p.S645P+p.S645Y+p.S645F
• Resistant Drug: Echinocandins
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Candida albicans strain; 5476
• Mechanism Description: For most Candida species, echinocandin resistance is primarily mediated by mutations in the FKS genes. In C. albicans, mutations that confer echinocandin resistance occur in the essential gene, FKS1. Hot-spot regions correspond to amino acids 641-649 (hot spot 1) and amino acids 1357-1364 (hot spot 2). Mutations at these regions decrease the IC50 of the glucan synthase enzyme by several orders of magnitude, elevate MIC values, and result in cross-resistance to diverse echinocandins. In C. albicans, serine 645 (S645) within hot-spot region 1 exhibits the highest frequency of substitution and is associated with the most prominent resistance phenotype.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Heat shock protein HSP 90 (HSP90 ) [2]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Echinocandins
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Candida albicans strain; 5476
• Mechanism Description: As discussed, Hsp90 regulates the function of calcineurin, as well as a number of stress-activated protein kinases, which is crucial in mediating responses to the echinocandins. Pharmacological or genetic impairment of Hsp90 function potentiates echinocandin activity in C. albicans, C. glabrata, and the distantly related pathogenic mold A. fumigatus. Furthermore, inhibition of Hsp90 reduces echinocandin resistance in C. glabrata clinical isolates with mutations in the echinocandin target gene FKS1.

Nocodazole

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Pleiotropic ABC efflux transporter of multiple drugs CDR1 (CDR1) [1]

• Sensitive Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Molecule Alteration: Deletion mutation; Deleteion
• Sensitive Drug: Nocodazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain DSY448; 5476
• Experiment for Molecule Alteration: PCR; Southern blotting analysis; Northern blottling analysis
• Experiment for Drug Resistance: Growth differences between the different C. albicans strains assay
• Mechanism Description: The delta cdr1 mutant was slightly more susceptible than the wild type to nocodazole, cerulenin, and crystal violet but not to amphotericin B, nikkomy- cin Z, flucytosine, or pradimicin.

References

• Ref 1: Susceptibilities of Candida albicans multidrug transporter mutants to various antifungal agents and other metabolic inhibitors. Antimicrob Agents Chemother. 1996 Oct;40(10):2300-5. doi: 10.1128/AAC.40.10.2300.
• Ref 2: Antifungal Drug Resistance: Molecular Mechanisms in Candida albicans and Beyond .Chem Rev. 2021 Mar 24;121(6):3390-3411. doi: 10.1021/acs.chemrev.0c00199. Epub 2020 May 22. 10.1021/acs.chemrev.0c00199
• Ref 3: Activity of CD101, a long-acting echinocandin, against clinical isolates of Candida auris. Diagn Microbiol Infect Dis. 2018 Mar;90(3):196-197. doi: 10.1016/j.diagmicrobio.2017.10.021. Epub 2017 Nov 7.
• Ref 4: A multicentre study of antifungal susceptibility patterns among 350 Candida auris isolates (2009-17) in India: role of the ERG11 and FKS1 genes in azole and echinocandin resistance. J Antimicrob Chemother. 2018 Apr 1;73(4):891-899. doi: 10.1093/jac/dkx480.
• Ref 5: Genomic epidemiology of the UK outbreak of the emerging human fungal pathogen Candida auris. Emerg Microbes Infect. 2018 Mar 29;7(1):43. doi: 10.1038/s41426-018-0045-x.
• Ref 6: Effect of Candida glabrata FKS1 and FKS2 mutations on echinocandin sensitivity and kinetics of 1,3-beta-D-glucan synthase: implication for the existing susceptibility breakpoint. Antimicrob Agents Chemother. 2009 Sep;53(9):3690-9. doi: 10.1128/AAC.00443-09. Epub 2009 Jun 22.
• Ref 7: Acquired echinocandin resistance in a Candida krusei isolate due to modification of glucan synthase. Antimicrob Agents Chemother. 2007 May;51(5):1876-8. doi: 10.1128/AAC.00067-07. Epub 2007 Feb 26.
• Ref 8: A naturally occurring proline-to-alanine amino acid change in Fks1p in Candida parapsilosis, Candida orthopsilosis, and Candida metapsilosis accounts for reduced echinocandin susceptibility. Antimicrob Agents Chemother. 2008 Jul;52(7):2305-12. doi: 10.1128/AAC.00262-08. Epub 2008 Apr 28.
• Ref 9: Specific substitutions in the echinocandin target Fks1p account for reduced susceptibility of rare laboratory and clinical Candida sp. isolates. Antimicrob Agents Chemother. 2005 Aug;49(8):3264-73. doi: 10.1128/AAC.49.8.3264-3273.2005.
• Ref 10: Assessing resistance to the echinocandin antifungal drug caspofungin in Candida albicans by profiling mutations in FKS1. Antimicrob Agents Chemother. 2006 Jun;50(6):2058-63. doi: 10.1128/AAC.01653-05.
• Ref 11: Application of real-time quantitative PCR to molecular analysis of Candida albicans strains exhibiting reduced susceptibility to azoles. Antimicrob Agents Chemother. 2004 Jun;48(6):2124-31. doi: 10.1128/AAC.48.6.2124-2131.2004.
• Ref 12: Amino acid substitutions in the cytochrome P-450 lanosterol 14alpha-demethylase (CYP51A1) from azole-resistant Candida albicans clinical isolates contribute to resistance to azole antifungal agents. Antimicrob Agents Chemother. 1998 Feb;42(2):241-53. doi: 10.1128/AAC.42.2.241.
• Ref 13: Susceptibility of clinical isolates of Candida species to fluconazole and detection of Candida albicans ERG11 mutations. J Antimicrob Chemother. 2008 Apr;61(4):798-804. doi: 10.1093/jac/dkn015. Epub 2008 Jan 24.
• Ref 14: Erg11 mutations associated with azole resistance in clinical isolates of Candida albicans. FEMS Yeast Res. 2013 Jun;13(4):386-93. doi: 10.1111/1567-1364.12042. Epub 2013 Apr 4.
• Ref 15: Simultaneous Emergence of Multidrug-Resistant Candida auris on 3 Continents Confirmed by Whole-Genome Sequencing and Epidemiological Analyses. Clin Infect Dis. 2017 Jan 15;64(2):134-140. doi: 10.1093/cid/ciw691. Epub 2016 Oct 20.
• Ref 16: Mechanisms of azole resistance in a clinical isolate of Candida tropicalis. Antimicrob Agents Chemother. 2005 Nov;49(11):4608-15. doi: 10.1128/AAC.49.11.4608-4615.2005.
• Ref 17: Evaluation of fluconazole resistance mechanisms in candida albicans clinical isolates from HIV-infected patients in Brazil. Diagn Microbiol Infect Dis. 2004 Sep;50(1):25-32. doi: 10.1016/j.diagmicrobio.2004.04.009.
• Ref 18: Multiple resistant phenotypes of Candida albicans coexist during episodes of oropharyngeal candidiasis in human immunodeficiency virus-infected patients. Antimicrob Agents Chemother. 1999 Jul;43(7):1621-30. doi: 10.1128/AAC.43.7.1621.
• Ref 19: Distinct patterns of gene expression associated with development of fluconazole resistance in serial candida albicans isolates from human immunodeficiency virus-infected patients with oropharyngeal candidiasis. Antimicrob Agents Chemother. 1998 Nov;42(11):2932-7. doi: 10.1128/AAC.42.11.2932.
• Ref 20: Multiple amino acid substitutions in lanosterol 14alpha-demethylase contribute to azole resistance in Candida albicans. Microbiology (Reading). 1999 Oct;145 ( Pt 10):2715-25. doi: 10.1099/00221287-145-10-2715.
• Ref 21: Mechanisms of resistance to azole antifungal agents in Candida albicans isolates from AIDS patients involve specific multidrug transporters. Antimicrob Agents Chemother. 1995 Nov;39(11):2378-86. doi: 10.1128/AAC.39.11.2378.
• Ref 22: Analysis of a Candida albicans gene that encodes a novel mechanism for resistance to benomyl and methotrexate. Mol Gen Genet. 1991 Jun;227(2):318-29. doi: 10.1007/BF00259685.
• Ref 23: Mutation in cytochrome P-450-dependent 14 alpha-demethylase results in decreased affinity for azole antifungals. Biochem Soc Trans. 1990 Feb;18(1):56-9. doi: 10.1042/bst0180056.
• Ref 24: Recurrent vulvovaginal candidiasis .Am J Obstet Gynecol. 2016 Jan;214(1):15-21. doi: 10.1016/j.ajog.2015.06.067. Epub 2015 Jul 9. 10.1016/j.ajog.2015.06.067
• Ref 25: Mutation of G234 amino acid residue in candida albicans drug-resistance-related protein Rta2p is associated with fluconazole resistance and dihydrosphingosine transport. Virulence. 2015;6(6):599-607. doi: 10.1080/21505594.2015.1051296.
• Ref 26: Clade-specific flucytosine resistance is due to a single nucleotide change in the FUR1 gene of Candida albicans. Antimicrob Agents Chemother. 2004 Jun;48(6):2223-7. doi: 10.1128/AAC.48.6.2223-2227.2004.