Drug Information

Drug (ID: DG00222) and It's Reported Resistant Information

• Name: Voriconazole
• Synonyms: VCZ; Vfend; Pfizer brand of voriconazole; UK 109496; Voriconazole in combination with MGCD290; DRG-0301; UK 109,496; UK-109496; VFEND (TN); Vfend (TN); Vfend, Voriconazole; UK-109,496; Voriconazole [USAN:INN:BAN]; Voriconazole (JAN/USAN/INN); (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1,2,4-triazol-1-yl)butan-2-ol; (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol; (R-(R*,S*))-alpha-(2,4-difluorophenyl)-5-fluoro-beta-methyl-alpha-(1H-1,2,4-triazol-1-ylmethyl)-4-pyrimidineethanol; (alphaR,betaS)-alpha-(2,4-Difluorophenyl)-5-fluoro-beta-methyl-alpha-(1H-1,2,4-triazol-1-ylmethyl)-4-pyrimidineethanol; (alphaR,betaS)-alpha-(2,4-difluorophenyl)-5-fluoro-beta-methyl-alpha(1H-1,2,4-triazol-1-ylmethyl)-4-pyrimidineethanol; VRC
• Indication:
  In total 1 Indication(s)
  Aspergillosis [ICD-11: 1F20]; Approved; [1]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (5 diseases)
  Aspergillosis [ICD-11: 1F20]; [2]
  Candidosis [ICD-11: 1F23]; [3]
  Dermatophytosis [ICD-11: 1F28]; [4]
  Histoplasmosis [ICD-11: 1F2A]; [5]
  Mycotic vaginitis [ICD-11: 1F2Y]; [6]
• Target: Candida Cytochrome P450 51 (Candi ERG11); CP51_CANAL; [1]
• Formula: C16H14F3N5O
• IsoSMILES: C[C@@H](C1=NC=NC=C1F)[C@](CN2C=NC=N2)(C3=C(C=C(C=C3)F)F)O
• InChI: 1S/C16H14F3N5O/c1-10(15-14(19)5-20-7-22-15)16(25,6-24-9-21-8-23-24)12-3-2-11(17)4-13(12)18/h2-5,7-10,25H,6H2,1H3/t10-,16+/m0/s1
• InChIKey: BCEHBSKCWLPMDN-MGPLVRAMSA-N
• PubChem CID: 71616
• ChEBI ID: CHEBI:10023
• TTD Drug ID: D0N3VR
• VARIDT ID: DR00445
• INTEDE ID: DR1709
• DrugBank ID: DB00582

Type(s) of Resistant Mechanism of This Drug

  ADTT: Aberration of the Drug's Therapeutic Target

  IDUE: Irregularity in Drug Uptake and Drug Efflux

Drug Resistance Data Categorized by Their Corresponding Diseases

ICD-01: Infectious/parasitic diseases

Aspergillosis [ICD-11: 1F20]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Sterol 14-alpha demethylase (CYP51C) [1]

• Molecule Alteration: Missense mutation; p.Y319H
• Resistant Disease: Aspergillus flavus infection [ICD-11: 1F20.1]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Aspergillus flavus strain; 5059
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: A novel Y319H substitution in CYP51C associated with azole resistance in Aspergillus flavus.

Key Molecule: Sterol 14-alpha demethylase cyp51A (CYP51A) [7]

• Molecule Alteration: Missense mutation; p.G138C
• Resistant Disease: Aspergillus fumigatus infection [ICD-11: 1F20.2]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Aspergillus fumigatus strain; 746128
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Multivariate analysis of overall survival or disease-free survival assay
• Mechanism Description: Each single mutationad a measurable effect on the affinity of the target enzyme for specific azole derivatives.

Key Molecule: Sterol 14-alpha demethylase cyp51A (CYP51A) [8]

• Molecule Alteration: Missense mutation; p.G448S
• Resistant Disease: Aspergillus fumigatus infection [ICD-11: 1F20.2]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Aspergillus fumigatus strain; 746128
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Resistance to voriconazole due to a G448S substitution in Aspergillus fumigatus in a patient with cerebral aspergillosis.

Key Molecule: Sterol 14-alpha demethylase cyp51A (CYP51A) [9]

• Molecule Alteration: Tandem repeat; TR53 (GAATCACGCGGTCCGATGTGTGCTGAGCCGAATGAAAGTTGTCTAATGTCTAGAATCACGCGGTCCGATGTGTGCTGAGCCGAATGAAAGTTGTCTAATGTCTA)
• Resistant Disease: Aspergillus fumigatus infection [ICD-11: 1F20.2]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Aspergillus fumigatus strain; 746128
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: The azole-resistant A. fumigatus strains were detected tandem repeats (TRs) in the promoter region.

Key Molecule: Sterol 14-alpha demethylase cyp51A (CYP51A) [2]

• Molecule Alteration: Missense mutation; p.G54R
• Resistant Disease: Invasive aspergillosis [ICD-11: 1F20.6]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Aspergillus fumigatus strain RIT; 746128
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: NCCLS M38-P microdilution methodology assay
• Mechanism Description: Itraconazole resistance has been tightly linked to cyp51A mutations in the codon for Gly54, resulting in five different amino substitutions (G54k, G54V, G54R, G54E, and G54W).

Key Molecule: Sterol 14-alpha demethylase cyp51A (CYP51A) [10]

• Molecule Alteration: Missense mutation; p.H147Y
• Resistant Disease: Invasive aspergillosis [ICD-11: 1F20.6]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Aspergillus fumigatus strain; 746128
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: EUCAST method assay
• Mechanism Description: Four novel mutations were found (H147Y, P216L, Y431C, and G434C). The isolate bearing the P216L mutation was resistant to itraconazole and posaconazole, whereas the isolates with Y431C and G434C showed pan-azole resistance phenotypes.

Key Molecule: Sterol 14-alpha demethylase cyp51A (CYP51A) [10]

• Molecule Alteration: Missense mutation; p.G434C
• Resistant Disease: Invasive aspergillosis [ICD-11: 1F20.6]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Aspergillus fumigatus strain; 746128
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: EUCAST method assay
• Mechanism Description: Four novel mutations were found (H147Y, P216L, Y431C, and G434C). The isolate bearing the P216L mutation was resistant to itraconazole and posaconazole, whereas the isolates with Y431C and G434C showed pan-azole resistance phenotypes.

Key Molecule: Sterol 14-alpha demethylase cyp51A (CYP51A) [10]

• Molecule Alteration: Missense mutation; p.Y431C
• Resistant Disease: Invasive aspergillosis [ICD-11: 1F20.6]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Aspergillus fumigatus strain; 746128
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: EUCAST method assay
• Mechanism Description: Four novel mutations were found (H147Y, P216L, Y431C, and G434C). The isolate bearing the P216L mutation was resistant to itraconazole and posaconazole, whereas the isolates with Y431C and G434C showed pan-azole resistance phenotypes.

Key Molecule: Sterol 14-alpha demethylase cyp51A (CYP51A) [11]

• Molecule Alteration: Missense mutation; p.Y121F+p.T289A+p.G448S+p.M172I
• Resistant Disease: Invasive aspergillosis [ICD-11: 1F20.6]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Aspergillus fumigatus strain TR463; 746128
• Experiment for Molecule Alteration: PCR analysis
• Mechanism Description: In addition, to compare the susceptibility of TR463 with those of TR34 and TR46, the high resistance of TR463/Y121F/M172I/T289A/G448S was confirmed by MIC testing, displaying a pan-triazole-resistant phenotype to posaconazole, itraconazole, and voriconazole, indicating no in vitro activity of itraconazole and voriconazole (MIC, >16 mg/liter).

Key Molecule: Sterol 14-alpha demethylase (CYP51C) [12]

• Molecule Alteration: Missense mutation; p.T788G
• Resistant Disease: Invasive aspergillosis [ICD-11: 1F20.6]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Aspergillus flavus strain; 5059
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: The T788G mutation in the cyp51C gene confers voriconazole resistance in aspergillus flavus causing aspergillosis.

Candidosis [ICD-11: 1F23]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

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

• Molecule Alteration: Missense mutation; p.Y132F
• Resistant Disease: Candida auris infection [ICD-11: 1F23.2]
• 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) [13]

• Molecule Alteration: Missense mutation; p.K143R
• Resistant Disease: Candida auris infection [ICD-11: 1F23.2]
• 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) [3]

• Molecule Alteration: Missense mutation; p.Y132H+p.G450E
• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• 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) [3]

• Molecule Alteration: Missense mutation; p.G450E+p.G464S
• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• 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) [3]

• Molecule Alteration: Missense mutation; p.Y132H+p.G448V
• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• 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) [3]

• Molecule Alteration: Missense mutation; p.S405F
• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• 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) [3]

• Molecule Alteration: Missense mutation; p.K128T+p.V452A
• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• 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) [3]

• Molecule Alteration: Missense mutation; p.Y132H+p.S405F
• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• 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) [3]

• Molecule Alteration: Missense mutation; p.G464S
• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• 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) [3]

• Molecule Alteration: Missense mutation; p.G464S+p.K128T+p.R467I
• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• 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) [3]

• Molecule Alteration: Missense mutation; p.Y257H+p.G464S
• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• 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) [3]

• Molecule Alteration: Missense mutation; p.A61V+p.Y257H+p.G464S+p.G307S
• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• 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) [3]

• Molecule Alteration: Missense mutation; p.Y257H+p.G464S+p.G307S
• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• 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) [3]

• Molecule Alteration: Missense mutation; p.K143R
• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• 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) [3]

• Molecule Alteration: Missense mutation; p.Y257H+p.Y132H+p.E266D
• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• 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) [3]

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

Dermatophytosis [ICD-11: 1F28]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Cuticle protein (TERG_08771 ) [4]

• Molecule Alteration: SNP; .
• Resistant Disease: Tinea capitis [ICD-11: 1F28.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Trichophyton rubrum isolates; 5551
• Experiment for Drug Resistance: Broth dilution method assay
• Mechanism Description: The gene TERG_08771 harboring the highest SNPs density is found to be associated with resistance to voriconazole.

Key Molecule: Cuticle protein (TERG_08771 ) [4]

• Molecule Alteration: SNP; .
• Resistant Disease: Tinea corporis [ICD-11: 1F28.Y]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Trichophyton rubrum isolates; 5551
• Experiment for Drug Resistance: Broth dilution method assay
• Mechanism Description: The gene TERG_08771 harboring the highest SNPs density is found to be associated with resistance to voriconazole.

Key Molecule: Cuticle protein (TERG_08771 ) [4]

• Molecule Alteration: SNP; .
• Resistant Disease: Tinea inguinalis [ICD-11: 1F28.4]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Trichophyton rubrum isolates; 5551
• Experiment for Drug Resistance: Broth dilution method assay
• Mechanism Description: The gene TERG_08771 harboring the highest SNPs density is found to be associated with resistance to voriconazole.

Key Molecule: Cuticle protein (TERG_08771 ) [4]

• Molecule Alteration: SNP; .
• Resistant Disease: Tinea manus [ICD-11: 1F28.5]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Trichophyton rubrum isolates; 5551
• Experiment for Drug Resistance: Broth dilution method assay
• Mechanism Description: The gene TERG_08771 harboring the highest SNPs density is found to be associated with resistance to voriconazole.

Key Molecule: Cuticle protein (TERG_08771 ) [4]

• Molecule Alteration: SNP; .
• Resistant Disease: Tinea pedis [ICD-11: 1F28.2]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Trichophyton rubrum isolates; 5551
• Experiment for Drug Resistance: Broth dilution method assay
• Mechanism Description: The gene TERG_08771 harboring the highest SNPs density is found to be associated with resistance to voriconazole.

Key Molecule: Cuticle protein (TERG_08771 ) [4]

• Molecule Alteration: SNP; .
• Resistant Disease: Tinea unguium [ICD-11: 1F28.1]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Trichophyton rubrum isolates; 5551
• Experiment for Drug Resistance: Broth dilution method assay
• Mechanism Description: The gene TERG_08771 harboring the highest SNPs density is found to be associated with resistance to voriconazole.

Histoplasmosis [ICD-11: 1F2A]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Cytochrome P450 sterol 14 alpha-demethylase (CYP51) [5]

• Molecule Alteration: Missense mutation; p.Y136F
• Resistant Disease: Histoplasmosis [ICD-11: 1F2A.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Histoplasma capsulatum strain; 5037
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: NCCLS method assay
• Mechanism Description: In summary, fluconazole treatment of disseminated histoplasmosis in patients with AIDS was associated with induction of resistance to fluconazole and, to a lesser extent, to voriconazole. And the changes in susceptibility were due to tagert alterations which a single amino acid substitution in CYP51p at Y136 appeared to be responsible for the reduction in susceptibility seen in the relapse isolate.

Mycotic vaginitis [ICD-11: 1F2Y]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [6]

• Molecule Alteration: Missense mutation; p.Y33C
• Resistant Disease: Mycotic vaginitis [ICD-11: 1F2Y.0]
• 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.

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [6]

• Molecule Alteration: Missense mutation; p.Y39C
• Resistant Disease: Mycotic vaginitis [ICD-11: 1F2Y.0]
• 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.

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [6]

• Molecule Alteration: Missense mutation; p.K119L
• Resistant Disease: Mycotic vaginitis [ICD-11: 1F2Y.0]
• 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.

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [6]

• Molecule Alteration: Missense mutation; p.T494A
• Resistant Disease: Mycotic vaginitis [ICD-11: 1F2Y.0]
• 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.

Key Molecule: Lanosterol 14-alpha demethylase (ERG11) [6]

• Molecule Alteration: Missense mutation; p.L491V
• Resistant Disease: Mycotic vaginitis [ICD-11: 1F2Y.0]
• 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.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein 1 (ABCB1) [6]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Mycotic vaginitis [ICD-11: 1F2Y.0]
• 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.

References

• Ref 1: A Novel Y319H Substitution in CYP51C Associated with Azole Resistance in Aspergillus flavus. Antimicrob Agents Chemother. 2015 Oct;59(10):6615-9. doi: 10.1128/AAC.00637-15. Epub 2015 Jul 27.
• Ref 2: Rapid, high-throughput, multiplex, real-time PCR for identification of mutations in the cyp51A gene of Aspergillus fumigatus that confer resistance to itraconazole. J Clin Microbiol. 2005 Jan;43(1):214-22. doi: 10.1128/JCM.43.1.214-222.2005.
• Ref 3: 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 4: Whole-genome resequencing of Trichophyton rubrum provides insights into population differentiation and drug resistance .Mycopathologia. 2020 Feb;185(1):103-112. doi: 10.1007/s11046-019-00384-1. Epub 2019 Sep 19. 10.1007/s11046-019-00384-1
• Ref 5: Activity of newer triazoles against Histoplasma capsulatum from patients with AIDS who failed fluconazole. J Antimicrob Chemother. 2006 Jun;57(6):1235-9. doi: 10.1093/jac/dkl133. Epub 2006 Apr 20.
• Ref 6: 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 7: Proposal for a unified nomenclature for target-site mutations associated with resistance to fungicides. Pest Manag Sci. 2016 Aug;72(8):1449-59. doi: 10.1002/ps.4301. Epub 2016 Jun 16.
• Ref 8: Resistance to voriconazole due to a G448S substitution in Aspergillus fumigatus in a patient with cerebral aspergillosis. J Clin Microbiol. 2012 Jul;50(7):2531-4. doi: 10.1128/JCM.00329-12. Epub 2012 May 9.
• Ref 9: Development and Validation of a High-Resolution Melting Assay To Detect Azole Resistance in Aspergillus fumigatus. Antimicrob Agents Chemother. 2017 Nov 22;61(12):e01083-17. doi: 10.1128/AAC.01083-17. Print 2017 Dec.
• Ref 10: Frequency and evolution of Azole resistance in Aspergillus fumigatus associated with treatment failure. Emerg Infect Dis. 2009 Jul;15(7):1068-76. doi: 10.3201/eid1507.090043.
• Ref 11: A Novel Environmental Azole Resistance Mutation in Aspergillus fumigatus and a Possible Role of Sexual Reproduction in Its Emergence. mBio. 2017 Jun 27;8(3):e00791-17. doi: 10.1128/mBio.00791-17.
• Ref 12: The T788G mutation in the cyp51C gene confers voriconazole resistance in Aspergillus flavus causing aspergillosis. Antimicrob Agents Chemother. 2012 May;56(5):2598-603. doi: 10.1128/AAC.05477-11. Epub 2012 Feb 6.
• Ref 13: 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.