Molecule Information

General Information of the Molecule (ID: Mol00985)

• Name: Lanosterol 14-alpha demethylase (ERG11) ,Candida albicans
• Synonyms: LDM; Cytochrome P450 51; Cytochrome P450-14DM; Cytochrome P450-LIA1; CYPLI; Ergosterol biosynthesis protein 11; Sterol 14-alpha demethylase; CYP51; ERG16; CAALFM_C500660CA; CaO19.922
• Molecule Type: Protein
• Gene Name: ERG11
• Gene ID: 3641571
• Sequence:
  MAIVETVIDGINYFLSLSVTQQISILLGVPFVYNLVWQYLYSLRKDRAPLVFYWIPWFGS
  AASYGQQPYEFFESCRQKYGDVFSFMLLGKIMTVYLGPKGHEFVFNAKLSDVSAEDAYKH
  LTTPVFGKGVIYDCPNSRLMEQKKFAKFALTTDSFKRYVPKIREEILNYFVTDESFKLKE
  KTHGVANVMKTQPEITIFTASRSLFGDEMRRIFDRSFAQLYSDLDKGFTPINFVFPNLPL
  PHYWRRDAAQKKISATYMKEIKSRRERGDIDPNRDLIDSLLIHSTYKDGVKMTDQEIANL
  LIGILMGGQHTSASTSAWFLLHLGEKPHLQDVIYQEVVELLKEKGGDLNDLTYEDLQKLP
  SVNNTIKETLRMHMPLHSIFRKVTNPLRIPETNYIVPKGHYVLVSPGYAHTSERYFDNPE
  DFDPTRWDTAAAKANSVSFNSSDEVDYGFGKVSKGVSSPYLPFGGGRHRCIGEQFAYVQL
  GTILTTFVYNLRWTIDGYKVPDPDYSSMVVLPTEPAEIIWEKRETCMF
• Function: Lanosterol 14-alpha demethylase; part of the third module of ergosterol biosynthesis pathway that includes the late steps of the pathway. The third module or late pathway involves the ergosterol synthesis itself through consecutive reactions that mainly occur in the endoplasmic reticulum (ER) membrane. Firstly, the squalene synthase ERG9 catalyzes the condensation of 2 farnesyl pyrophosphate moieties to form squalene, which is the precursor of all steroids. Squalene synthase is crucial for balancing the incorporation of farnesyl diphosphate (FPP) into sterol and nonsterol isoprene synthesis. Secondly, the squalene epoxidase ERG1 catalyzes the stereospecific oxidation of squalene to (S)-2,3-epoxysqualene, which is considered to be a rate-limiting enzyme in steroid biosynthesis. Then, the lanosterol synthase ERG7 catalyzes the cyclization of (S)-2,3 oxidosqualene to lanosterol, a reaction that forms the sterol core. In the next steps, lanosterol is transformed to zymosterol through a complex process involving various demethylation, reduction and desaturation reactions. The lanosterol 14-alpha-demethylase ERG11 (also known as CYP51) catalyzes C14-demethylation of lanosterol to produce 4,4'-dimethyl cholesta-8,14,24-triene-3-beta-ol, which is critical for ergosterol biosynthesis. The C-14 reductase ERG24 reduces the C14=C15 double bond of 4,4-dimethyl-cholesta-8,14,24-trienol to produce 4,4-dimethyl-cholesta-8,24-dienol. 4,4-dimethyl-cholesta-8,24-dienol is substrate of the C-4 demethylation complex ERG25-ERG26-ERG27 in which ERG25 catalyzes the three-step monooxygenation required for the demethylation of 4,4-dimethyl and 4alpha-methylsterols, ERG26 catalyzes the oxidative decarboxylation that results in a reduction of the 3-beta-hydroxy group at the C-3 carbon to an oxo group, and ERG27 is responsible for the reduction of the keto group on the C-3. ERG28 has a role as a scaffold to help anchor ERG25, ERG26 and ERG27 to the endoplasmic reticulum and ERG29 regulates the activity of the iron-containing C4-methylsterol oxidase ERG25. Then, the sterol 24-C-methyltransferase ERG6 catalyzes the methyl transfer from S-adenosyl-methionine to the C-24 of zymosterol to form fecosterol. The C-8 sterol isomerase ERG2 catalyzes the reaction which results in unsaturation at C-7 in the B ring of sterols and thus converts fecosterol to episterol. The sterol-C5-desaturase ERG3 then catalyzes the introduction of a C-5 double bond in the B ring to produce 5-dehydroepisterol. The C-22 sterol desaturase ERG5 further converts 5-dehydroepisterol into ergosta-5,7,22,24(28)-tetraen-3beta-ol by forming the C-22(23) double bond in the sterol side chain. Finally, ergosta-5,7,22,24(28)-tetraen-3beta-ol is substrate of the C-24(28) sterol reductase ERG4 to produce ergosterol.
• Uniprot ID: CP51_CANAL

Kingdom: Fungi
Phylum: Ascomycota
Class: Saccharomycetes
Order: Saccharomycetales
Family: Debaryomycetaceae
Genus: Candida
Species: Candida albicans

Type(s) of Resistant Mechanism of This Molecule

  ADTT: Aberration of the Drug's Therapeutic Target

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

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

Amphotericin B

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Recurrent oropharyngeal candidiasis [1]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Resistant Drug: Amphotericin B
• Molecule Alteration: Missense mutation; p.A114S
• 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.

Fluconazole

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Recurrent oropharyngeal candidiasis [2], [3]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Resistant Drug: Fluconazole
• Molecule Alteration: Missense mutation; p.S405F
• 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).

Disease Class: Recurrent oropharyngeal candidiasis [2], [3]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Resistant Drug: Fluconazole
• Molecule Alteration: Missense mutation; p.G464S
• 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).

Disease Class: Candida albicans infection [4]

• Resistant Disease: Candida albicans infection [ICD-11: 1F23.Y]
• Resistant Drug: Fluconazole
• Molecule Alteration: Missense mutation; p.A114S+p.Y257H+p.G487T+p.T916C
• 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.

Disease Class: Candida albicans infection [4]

• Resistant Disease: Candida albicans infection [ICD-11: 1F23.Y]
• Resistant Drug: Fluconazole
• Molecule Alteration: Missense mutation; p.M140R
• 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.

Disease Class: Candida albicans infection [4]

• Resistant Disease: Candida albicans infection [ICD-11: 1F23.Y]
• Resistant Drug: Fluconazole
• Molecule Alteration: Missense mutation; p.K161N
• 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.

Disease Class: Candida albicans infection [4]

• Resistant Disease: Candida albicans infection [ICD-11: 1F23.Y]
• Resistant Drug: Fluconazole
• Molecule Alteration: Missense mutation; p.R163T
• 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.

Disease Class: Candida albicans infection [4]

• Resistant Disease: Candida albicans infection [ICD-11: 1F23.Y]
• Resistant Drug: Fluconazole
• Molecule Alteration: Missense mutation; p.E165K
• 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.

Disease Class: Candida albicans infection [4]

• Resistant Disease: Candida albicans infection [ICD-11: 1F23.Y]
• Resistant Drug: Fluconazole
• Molecule Alteration: Missense mutation; p.D225Y
• 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.

Disease Class: Candida albicans infection [4]

• Resistant Disease: Candida albicans infection [ICD-11: 1F23.Y]
• Resistant Drug: Fluconazole
• Molecule Alteration: Missense mutation; p.D225H
• 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.

Disease Class: Candida albicans infection [4]

• Resistant Disease: Candida albicans infection [ICD-11: 1F23.Y]
• Resistant Drug: Fluconazole
• Molecule Alteration: Missense mutation; p.F449Y
• 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.

Disease Class: Candida albicans infection [4]

• Resistant Disease: Candida albicans infection [ICD-11: 1F23.Y]
• Resistant Drug: Fluconazole
• Molecule Alteration: Missense mutation; p.I471T
• 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.

Disease Class: Candida albicans infection [4]

• Resistant Disease: Candida albicans infection [ICD-11: 1F23.Y]
• Resistant Drug: Fluconazole
• Molecule Alteration: Missense mutation; p.Q474K
• 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.

Disease Class: Candida albicans infection [4]

• Resistant Disease: Candida albicans infection [ICD-11: 1F23.Y]
• Resistant Drug: Fluconazole
• Molecule Alteration: Missense mutation; p.P375Q
• 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.

Disease Class: Candida albicans infection [4]

• Resistant Disease: Candida albicans infection [ICD-11: 1F23.Y]
• Resistant Drug: Fluconazole
• Molecule Alteration: Missense mutation; p.R381I
• 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.

Disease Class: Candida albicans infection [4]

• Resistant Disease: Candida albicans infection [ICD-11: 1F23.Y]
• Resistant Drug: Fluconazole
• Molecule Alteration: Missense mutation; p.K119N
• 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.

Disease Class: Candida albicans infection [5]

• Resistant Disease: Candida albicans infection [ICD-11: 1F23.Y]
• Resistant Drug: Fluconazole
• Molecule Alteration: Missense mutation; p.Y132F+p.Y205E+p.Y257H+p.D116E+p.K143Q
• 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).

Disease Class: Candida albicans infection [5]

• Resistant Disease: Candida albicans infection [ICD-11: 1F23.Y]
• Resistant Drug: Fluconazole
• Molecule Alteration: Missense mutation; p.Y132F+p.Y205E+p.V437I+p.D116E+p.K143Q
• 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).

Disease Class: Candidosis [6]

• Resistant Disease: Candidosis [ICD-11: 1F23.0]
• Resistant Drug: Fluconazole
• Molecule Alteration: Missense mutation; p.F380S
• 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.

Disease Class: Candidosis [6]

• Resistant Disease: Candidosis [ICD-11: 1F23.0]
• Resistant Drug: Fluconazole
• Molecule Alteration: Missense mutation; p.Y132F+p.F145L
• 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.

Disease Class: Candidosis [6]

• Resistant Disease: Candidosis [ICD-11: 1F23.0]
• Resistant Drug: Fluconazole
• Molecule Alteration: Missense mutation; p.Y79C+p.T199I
• 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.

Disease Class: Candidosis [6]

• Resistant Disease: Candidosis [ICD-11: 1F23.0]
• Resistant Drug: Fluconazole
• Molecule Alteration: Missense mutation; p.V437I+p.I253V
• 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.

Disease Class: Candidosis [6]

• Resistant Disease: Candidosis [ICD-11: 1F23.0]
• Resistant Drug: Fluconazole
• Molecule Alteration: Missense mutation; p.E266D+p.V488I+p.V130I
• 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.

Disease Class: Candidosis [6]

• Resistant Disease: Candidosis [ICD-11: 1F23.0]
• Resistant Drug: Fluconazole
• Molecule Alteration: Missense mutation; p.K143E+p.P503L
• 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.

Disease Class: Candidosis [6]

• Resistant Disease: Candidosis [ICD-11: 1F23.0]
• Resistant Drug: Fluconazole
• Molecule Alteration: Expression; Up-regulation
• 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.

Disease Class: Mycotic vaginitis [7]

• Resistant Disease: Mycotic vaginitis [ICD-11: 1F2Y.0]
• Resistant Drug: Fluconazole
• Molecule Alteration: Missense mutation; p.Y33C
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain; 5476
• Experiment for Molecule Alteration: Northern blot analysis; DNA sequencing assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Resistance mechanisms that have been identified include overexpression of the MDR1 gene encoding a drug efflux pump, increased expression of the CDR1 and CDR2 genes, overexpression of the ERG11 gene coding for the FLU target enzyme, and alterations in the structure of Erg11p.

Disease Class: Mycotic vaginitis [7]

• Resistant Disease: Mycotic vaginitis [ICD-11: 1F2Y.0]
• Resistant Drug: Fluconazole
• Molecule Alteration: Missense mutation; p.Y39C
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain; 5476
• Experiment for Molecule Alteration: Northern blot analysis; DNA sequencing assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Resistance mechanisms that have been identified include overexpression of the MDR1 gene encoding a drug efflux pump, increased expression of the CDR1 and CDR2 genes, overexpression of the ERG11 gene coding for the FLU target enzyme, and alterations in the structure of Erg11p.

Disease Class: Mycotic vaginitis [7]

• Resistant Disease: Mycotic vaginitis [ICD-11: 1F2Y.0]
• Resistant Drug: Fluconazole
• Molecule Alteration: Missense mutation; p.K119L
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain; 5476
• Experiment for Molecule Alteration: Northern blot analysis; DNA sequencing assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Resistance mechanisms that have been identified include overexpression of the MDR1 gene encoding a drug efflux pump, increased expression of the CDR1 and CDR2 genes, overexpression of the ERG11 gene coding for the FLU target enzyme, and alterations in the structure of Erg11p.

Disease Class: Mycotic vaginitis [7]

• Resistant Disease: Mycotic vaginitis [ICD-11: 1F2Y.0]
• Resistant Drug: Fluconazole
• Molecule Alteration: Missense mutation; p.T494A
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain; 5476
• Experiment for Molecule Alteration: Northern blot analysis; DNA sequencing assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Resistance mechanisms that have been identified include overexpression of the MDR1 gene encoding a drug efflux pump, increased expression of the CDR1 and CDR2 genes, overexpression of the ERG11 gene coding for the FLU target enzyme, and alterations in the structure of Erg11p.

Disease Class: Mycotic vaginitis [7]

• Resistant Disease: Mycotic vaginitis [ICD-11: 1F2Y.0]
• Resistant Drug: Fluconazole
• Molecule Alteration: Missense mutation; p.L491V
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain; 5476
• Experiment for Molecule Alteration: Northern blot analysis; DNA sequencing assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Resistance mechanisms that have been identified include overexpression of the MDR1 gene encoding a drug efflux pump, increased expression of the CDR1 and CDR2 genes, overexpression of the ERG11 gene coding for the FLU target enzyme, and alterations in the structure of Erg11p.

Disease Class: Mycotic vaginitis [7]

• Resistant Disease: Mycotic vaginitis [ICD-11: 1F2Y.0]
• Resistant Drug: Fluconazole
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain; 5476
• Experiment for Molecule Alteration: Northern blot analysis
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Resistance mechanisms that have been identified include overexpression of the MDR1 gene encoding a drug efflux pump, increased expression of the CDR1 and CDR2 genes, overexpression of the ERG11 gene coding for the FLU target enzyme, and alterations in the structure of Erg11p.

Disease Class: Recurrent oropharyngeal candidiasis [3]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Resistant Drug: Fluconazole
• Molecule Alteration: Missense mutation; p.G464S+p.R467K
• 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.

Disease Class: Recurrent oropharyngeal candidiasis [3]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Resistant Drug: Fluconazole
• Molecule Alteration: Missense mutation; p.G464S+p.G129A
• 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.

Disease Class: Recurrent oropharyngeal candidiasis [3]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Resistant Drug: Fluconazole
• Molecule Alteration: Missense mutation; p.Y132H
• 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.

Disease Class: Recurrent oropharyngeal candidiasis [3]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Resistant Drug: Fluconazole
• Molecule Alteration: Missense mutation; p.S405F+p.Y132H
• 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.

Disease Class: Recurrent oropharyngeal candidiasis [3]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Resistant Drug: Fluconazole
• Molecule Alteration: Missense mutation; p.G464S+p.Y132H
• 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.

Disease Class: Recurrent oropharyngeal candidiasis [3]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Resistant Drug: Fluconazole
• Molecule Alteration: Missense mutation; p.R467K
• 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.

Disease Class: Recurrent oropharyngeal candidiasis [2]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Resistant Drug: Fluconazole
• Molecule Alteration: Missense mutation; p.Y132H+p.G450E
• 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).

Disease Class: Recurrent oropharyngeal candidiasis [2]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Resistant Drug: Fluconazole
• Molecule Alteration: Missense mutation; p.G450E+p.G464S
• 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).

Disease Class: Recurrent oropharyngeal candidiasis [2]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Resistant Drug: Fluconazole
• Molecule Alteration: Missense mutation; p.Y132H+p.G448V
• 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).

Disease Class: Recurrent oropharyngeal candidiasis [2]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Resistant Drug: Fluconazole
• Molecule Alteration: Missense mutation; p.K128T+p.V452A
• 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).

Disease Class: Recurrent oropharyngeal candidiasis [2]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Resistant Drug: Fluconazole
• Molecule Alteration: Missense mutation; p.Y132H+p.S405F
• 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).

Disease Class: Recurrent oropharyngeal candidiasis [2]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Resistant Drug: Fluconazole
• Molecule Alteration: Missense mutation; p.G464S+p.K128T+p.R467I
• 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).

Disease Class: Recurrent oropharyngeal candidiasis [2]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Resistant Drug: Fluconazole
• Molecule Alteration: Missense mutation; p.Y257H+p.G464S
• 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).

Disease Class: Recurrent oropharyngeal candidiasis [2]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Resistant Drug: Fluconazole
• Molecule Alteration: Missense mutation; p.A61V+p.Y257H+p.G464S+p.G307S
• 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).

Disease Class: Recurrent oropharyngeal candidiasis [2]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Resistant Drug: Fluconazole
• Molecule Alteration: Missense mutation; p.Y257H+p.G464S+p.G307S
• 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).

Disease Class: Recurrent oropharyngeal candidiasis [2]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Resistant Drug: Fluconazole
• Molecule Alteration: Missense mutation; p.K143R
• 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).

Disease Class: Recurrent oropharyngeal candidiasis [2]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Resistant Drug: Fluconazole
• Molecule Alteration: Missense mutation; p.Y257H+p.Y132H+p.E266D
• 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).

Disease Class: Recurrent oropharyngeal candidiasis [2]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Resistant Drug: Fluconazole
• Molecule Alteration: Missense mutation; p.Y132H+p.G464S+p.H283R
• 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).

Disease Class: Recurrent oropharyngeal candidiasis [2], [8], [9]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Resistant Drug: Fluconazole
• Molecule Alteration: Expression; Up-regulation
• 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.

Disease Class: Recurrent oropharyngeal candidiasis [10]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Resistant Drug: Fluconazole
• Molecule Alteration: Missense mutation; p.F72L
• 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.

Disease Class: Recurrent oropharyngeal candidiasis [10]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Resistant Drug: Fluconazole
• Molecule Alteration: Missense mutation; p.T132H
• 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.

Disease Class: Recurrent oropharyngeal candidiasis [10]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Resistant Drug: Fluconazole
• Molecule Alteration: Missense mutation; p.F126L
• 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.

Disease Class: Recurrent oropharyngeal candidiasis [10]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Resistant Drug: Fluconazole
• Molecule Alteration: Missense mutation; p.E266D
• 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.

Disease Class: Recurrent oropharyngeal candidiasis [10]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Resistant Drug: Fluconazole
• Molecule Alteration: Missense mutation; p.V437I
• 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.

Disease Class: Recurrent oropharyngeal candidiasis [10]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Resistant Drug: Fluconazole
• Molecule Alteration: Missense mutation; p.F449L
• 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.

Disease Class: Recurrent oropharyngeal candidiasis [10]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Resistant Drug: Fluconazole
• Molecule Alteration: Missense mutation; p.K143E
• 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.

Disease Class: Recurrent oropharyngeal candidiasis [10]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Resistant Drug: Fluconazole
• Molecule Alteration: Missense mutation; p.T229A
• 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.

Disease Class: Recurrent oropharyngeal candidiasis [1]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Resistant Drug: Fluconazole
• Molecule Alteration: Expression; Up-regulation
• 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.

Itraconazole

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Candida albicans infection [5]

• Resistant Disease: Candida albicans infection [ICD-11: 1F23.Y]
• Resistant Drug: Itraconazole
• Molecule Alteration: Missense mutation; p.Y132F+p.Y205E+p.Y257H+p.D116E+p.K143Q
• 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).

Disease Class: Candida albicans infection [5]

• Resistant Disease: Candida albicans infection [ICD-11: 1F23.Y]
• Resistant Drug: Itraconazole
• Molecule Alteration: Missense mutation; p.Y132F+p.Y205E+p.V437I+p.D116E+p.K143Q
• 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).

Disease Class: Candida albicans infection [5]

• Resistant Disease: Candida albicans infection [ICD-11: 1F23.Y]
• Resistant Drug: Itraconazole
• Molecule Alteration: Missense mutation; p.A114S+p.Y205E+p.Y257H+p.V437I
• 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).

Disease Class: Candida albicans infection [5]

• Resistant Disease: Candida albicans infection [ICD-11: 1F23.Y]
• Resistant Drug: Itraconazole
• Molecule Alteration: Missense mutation; p.Y205E+p.V437I+p.Y132H+p.G472R
• 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).

Disease Class: Mycotic vaginitis [7]

• Resistant Disease: Mycotic vaginitis [ICD-11: 1F2Y.0]
• Resistant Drug: Itraconazole
• Molecule Alteration: Missense mutation; p.P49R+p.E266D+p.T486P+p.V488I
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain; 5476
• Experiment for Molecule Alteration: Northern blot analysis; DNA sequencing assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Resistance mechanisms that have been identified include overexpression of the MDR1 gene encoding a drug efflux pump, increased expression of the CDR1 and CDR2 genes, overexpression of the ERG11 gene coding for the FLU target enzyme, and alterations in the structure of Erg11p.

Disease Class: Mycotic vaginitis [7]

• Resistant Disease: Mycotic vaginitis [ICD-11: 1F2Y.0]
• Resistant Drug: Itraconazole
• Molecule Alteration: Missense mutation; p.Y33C
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain; 5476
• Experiment for Molecule Alteration: Northern blot analysis; DNA sequencing assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Resistance mechanisms that have been identified include overexpression of the MDR1 gene encoding a drug efflux pump, increased expression of the CDR1 and CDR2 genes, overexpression of the ERG11 gene coding for the FLU target enzyme, and alterations in the structure of Erg11p.

Disease Class: Mycotic vaginitis [7]

• Resistant Disease: Mycotic vaginitis [ICD-11: 1F2Y.0]
• Resistant Drug: Itraconazole
• Molecule Alteration: Missense mutation; p.Y39C
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain; 5476
• Experiment for Molecule Alteration: Northern blot analysis; DNA sequencing assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Resistance mechanisms that have been identified include overexpression of the MDR1 gene encoding a drug efflux pump, increased expression of the CDR1 and CDR2 genes, overexpression of the ERG11 gene coding for the FLU target enzyme, and alterations in the structure of Erg11p.

Disease Class: Mycotic vaginitis [7]

• Resistant Disease: Mycotic vaginitis [ICD-11: 1F2Y.0]
• Resistant Drug: Itraconazole
• Molecule Alteration: Missense mutation; p.K119L
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain; 5476
• Experiment for Molecule Alteration: Northern blot analysis; DNA sequencing assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Resistance mechanisms that have been identified include overexpression of the MDR1 gene encoding a drug efflux pump, increased expression of the CDR1 and CDR2 genes, overexpression of the ERG11 gene coding for the FLU target enzyme, and alterations in the structure of Erg11p.

Disease Class: Mycotic vaginitis [7]

• Resistant Disease: Mycotic vaginitis [ICD-11: 1F2Y.0]
• Resistant Drug: Itraconazole
• Molecule Alteration: Missense mutation; p.T494A
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain; 5476
• Experiment for Molecule Alteration: Northern blot analysis; DNA sequencing assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Resistance mechanisms that have been identified include overexpression of the MDR1 gene encoding a drug efflux pump, increased expression of the CDR1 and CDR2 genes, overexpression of the ERG11 gene coding for the FLU target enzyme, and alterations in the structure of Erg11p.

Disease Class: Mycotic vaginitis [7]

• Resistant Disease: Mycotic vaginitis [ICD-11: 1F2Y.0]
• Resistant Drug: Itraconazole
• Molecule Alteration: Missense mutation; p.L491V
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain; 5476
• Experiment for Molecule Alteration: Northern blot analysis; DNA sequencing assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Resistance mechanisms that have been identified include overexpression of the MDR1 gene encoding a drug efflux pump, increased expression of the CDR1 and CDR2 genes, overexpression of the ERG11 gene coding for the FLU target enzyme, and alterations in the structure of Erg11p.

Disease Class: Recurrent oropharyngeal candidiasis [3]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Resistant Drug: Itraconazole
• Molecule Alteration: Missense mutation; p.Y132H
• 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.

Disease Class: Recurrent oropharyngeal candidiasis [3]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Resistant Drug: Itraconazole
• Molecule Alteration: Missense mutation; p.G464S
• 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.

Disease Class: Recurrent oropharyngeal candidiasis [3]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Resistant Drug: Itraconazole
• Molecule Alteration: Missense mutation; p.R467K
• 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.

Disease Class: Recurrent oropharyngeal candidiasis [3]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Resistant Drug: Itraconazole
• Molecule Alteration: Missense mutation; p.S405F+p.Y132H
• 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.

Disease Class: Recurrent oropharyngeal candidiasis [3]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Resistant Drug: Itraconazole
• Molecule Alteration: Missense mutation; p.G464S+p.Y132H
• 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.

Disease Class: Recurrent oropharyngeal candidiasis [3]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Resistant Drug: Itraconazole
• Molecule Alteration: Missense mutation; p.G464S+p.R467K
• 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.

Ketoconazole

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Recurrent oropharyngeal candidiasis [3]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Resistant Drug: Ketoconazole
• Molecule Alteration: Missense mutation; p.Y132H
• 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.

Disease Class: Recurrent oropharyngeal candidiasis [3]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Resistant Drug: Ketoconazole
• Molecule Alteration: Missense mutation; p.S405F+p.Y132H
• 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.

Disease Class: Recurrent oropharyngeal candidiasis [3]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Resistant Drug: Ketoconazole
• Molecule Alteration: Missense mutation; p.G464S+p.Y132H
• 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.

Disease Class: Recurrent oropharyngeal candidiasis [3]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Resistant Drug: Ketoconazole
• Molecule Alteration: Missense mutation; p.G464S+p.R467K
• 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.

Disease Class: Recurrent oropharyngeal candidiasis [3]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Resistant Drug: Ketoconazole
• Molecule Alteration: Missense mutation; p.G464S+p.G129A
• 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.

Voriconazole

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Mycotic vaginitis [7]

• Resistant Disease: Mycotic vaginitis [ICD-11: 1F2Y.0]
• Resistant Drug: Voriconazole
• Molecule Alteration: Missense mutation; p.Y33C
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain; 5476
• Experiment for Molecule Alteration: Northern blot analysis; DNA sequencing assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Resistance mechanisms that have been identified include overexpression of the MDR1 gene encoding a drug efflux pump, increased expression of the CDR1 and CDR2 genes, overexpression of the ERG11 gene coding for the FLU target enzyme, and alterations in the structure of Erg11p.

Disease Class: Mycotic vaginitis [7]

• Resistant Disease: Mycotic vaginitis [ICD-11: 1F2Y.0]
• Resistant Drug: Voriconazole
• Molecule Alteration: Missense mutation; p.Y39C
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain; 5476
• Experiment for Molecule Alteration: Northern blot analysis; DNA sequencing assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Resistance mechanisms that have been identified include overexpression of the MDR1 gene encoding a drug efflux pump, increased expression of the CDR1 and CDR2 genes, overexpression of the ERG11 gene coding for the FLU target enzyme, and alterations in the structure of Erg11p.

Disease Class: Mycotic vaginitis [7]

• Resistant Disease: Mycotic vaginitis [ICD-11: 1F2Y.0]
• Resistant Drug: Voriconazole
• Molecule Alteration: Missense mutation; p.K119L
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain; 5476
• Experiment for Molecule Alteration: Northern blot analysis; DNA sequencing assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Resistance mechanisms that have been identified include overexpression of the MDR1 gene encoding a drug efflux pump, increased expression of the CDR1 and CDR2 genes, overexpression of the ERG11 gene coding for the FLU target enzyme, and alterations in the structure of Erg11p.

Disease Class: Mycotic vaginitis [7]

• Resistant Disease: Mycotic vaginitis [ICD-11: 1F2Y.0]
• Resistant Drug: Voriconazole
• Molecule Alteration: Missense mutation; p.T494A
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain; 5476
• Experiment for Molecule Alteration: Northern blot analysis; DNA sequencing assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Resistance mechanisms that have been identified include overexpression of the MDR1 gene encoding a drug efflux pump, increased expression of the CDR1 and CDR2 genes, overexpression of the ERG11 gene coding for the FLU target enzyme, and alterations in the structure of Erg11p.

Disease Class: Mycotic vaginitis [7]

• Resistant Disease: Mycotic vaginitis [ICD-11: 1F2Y.0]
• Resistant Drug: Voriconazole
• Molecule Alteration: Missense mutation; p.L491V
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain; 5476
• Experiment for Molecule Alteration: Northern blot analysis; DNA sequencing assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Resistance mechanisms that have been identified include overexpression of the MDR1 gene encoding a drug efflux pump, increased expression of the CDR1 and CDR2 genes, overexpression of the ERG11 gene coding for the FLU target enzyme, and alterations in the structure of Erg11p.

Disease Class: Recurrent oropharyngeal candidiasis [2]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Resistant Drug: Voriconazole
• Molecule Alteration: Missense mutation; p.Y132H+p.G450E
• 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).

Disease Class: Recurrent oropharyngeal candidiasis [2]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Resistant Drug: Voriconazole
• Molecule Alteration: Missense mutation; p.G450E+p.G464S
• 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).

Disease Class: Recurrent oropharyngeal candidiasis [2]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Resistant Drug: Voriconazole
• Molecule Alteration: Missense mutation; p.Y132H+p.G448V
• 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).

Disease Class: Recurrent oropharyngeal candidiasis [2]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Resistant Drug: Voriconazole
• Molecule Alteration: Missense mutation; p.S405F
• 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).

Disease Class: Recurrent oropharyngeal candidiasis [2]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Resistant Drug: Voriconazole
• Molecule Alteration: Missense mutation; p.K128T+p.V452A
• 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).

Disease Class: Recurrent oropharyngeal candidiasis [2]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Resistant Drug: Voriconazole
• Molecule Alteration: Missense mutation; p.Y132H+p.S405F
• 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).

Disease Class: Recurrent oropharyngeal candidiasis [2]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Resistant Drug: Voriconazole
• Molecule Alteration: Missense mutation; p.G464S
• 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).

Disease Class: Recurrent oropharyngeal candidiasis [2]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Resistant Drug: Voriconazole
• Molecule Alteration: Missense mutation; p.G464S+p.K128T+p.R467I
• 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).

Disease Class: Recurrent oropharyngeal candidiasis [2]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Resistant Drug: Voriconazole
• Molecule Alteration: Missense mutation; p.Y257H+p.G464S
• 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).

Disease Class: Recurrent oropharyngeal candidiasis [2]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Resistant Drug: Voriconazole
• Molecule Alteration: Missense mutation; p.A61V+p.Y257H+p.G464S+p.G307S
• 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).

Disease Class: Recurrent oropharyngeal candidiasis [2]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Resistant Drug: Voriconazole
• Molecule Alteration: Missense mutation; p.Y257H+p.G464S+p.G307S
• 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).

Disease Class: Recurrent oropharyngeal candidiasis [2]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Resistant Drug: Voriconazole
• Molecule Alteration: Missense mutation; p.K143R
• 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).

Disease Class: Recurrent oropharyngeal candidiasis [2]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Resistant Drug: Voriconazole
• Molecule Alteration: Missense mutation; p.Y257H+p.Y132H+p.E266D
• 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).

Disease Class: Recurrent oropharyngeal candidiasis [2]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Resistant Drug: Voriconazole
• Molecule Alteration: Missense mutation; p.Y132H+p.G464S+p.H283R
• 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).

References

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• Ref 7: Resistance mechanisms in fluconazole-resistant Candida albicans isolates from vaginal candidiasis. Int J Antimicrob Agents. 2006 May;27(5):403-8. doi: 10.1016/j.ijantimicag.2005.12.005. Epub 2006 Apr 18.
• Ref 8: 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 9: 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 10: 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.