Molecule Information

General Information of the Molecule (ID: Mol00986)

• Name: Lanosterol 14-alpha demethylase (ERG11) ,Candida auris
• Synonyms: 14-alpha-demethylase; B9J08_001448
• Molecule Type: Protein
• Gene Name: ERG11
• Sequence:
  MALKDCIVDVVDRFSALPVPVKLAVLILVPIVYNLVWQFVYSLRKDRAPLVFHWVPWVGS
  AVVYGMQPYQFFESCREKYGDVFAFVMLGKVMTVYLGPKGHEFVLNAKLADVSAEAAYSH
  LTTPVFGKGVIYDCPNSRLMEQKKFAKTALTKEAFQRYVPRIQEEVLDYFKACSQFKMNE
  RNNGVANVMKTQPEMTILTASKSLMGDDMRARFDASFAKLYSDLDKGFTPINFVFPHLPL
  PAYWKRDAAQQKISATYMSLINERRKTGDIVPDRDLIDSLMTNSTYKDGVKMTDQEVANL
  LIGVLMGGQHTSASTSAWFLLHLAEQPKLQEELYNEVLSVLAEKGGSLKDLAYDDLQKMP
  LINQTIKETLRLHMPLHSIFRKVMNPLVVPNTKYVVPKGHYVMVSPGYAQTNEKWFPRAN
  EFDPHRWDEETSSNIDTDAVDYGFGKVTKGVSSPYLPFGGGRHRCIGEQFAYVQLGTILA
  TYVYNIKWRFKKDGSLPPVDYQSMVTLPMEPAEIEWEKRETCVY
• Uniprot ID: A0A2H1A309_CANAR

Kingdom: Fungi
Phylum: Ascomycota
Class: Saccharomycetes
Order: Saccharomycetales
Family: Metschnikowiaceae
Genus: .
Species: Candida auris

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

Fluconazole

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Candida auris infection [ICD-11: 1F23.2] [1]

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

Disease Class: Candida auris infection [ICD-11: 1F23.2] [1]

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

Disease Class: Candida auris infection [ICD-11: 1F23.2] [1]

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

Disease Class: Candida auris infection [ICD-11: 1F23.2] [2]

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

Disease Class: Candida auris infection [ICD-11: 1F23.2] [2]

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

Disease Class: Cryptococcal meningitis [ICD-11: 1D01.0] [3]

• Resistant Disease: Cryptococcal meningitis [ICD-11: 1D01.0]
• Resistant Drug: Fluconazole
• Molecule Alteration: Missense mutation; p.G484S (c.G1855T)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Cryptococcus neoformans stiain CN-5; 5207
• Experiment for Molecule Alteration: Genomic sequence assay
• Experiment for Drug Resistance: Microdilution and E-test methods assay
• Mechanism Description: A point mutation (G1855T) in the ERG11 gene was detected in the FCZ-resistant isolate (CN-5) only. And this mutation is responsible for the amino acid substitution glycine 484 for serine (G484S) in the ERG11 deduced protein sequence of C. neoformans.

Disease Class: Histoplasmosis [ICD-11: 1F2A.0] [4]

• Resistant Disease: Histoplasmosis [ICD-11: 1F2A.0]
• Resistant Drug: Fluconazole
• Molecule Alteration: Missense mutation; p.Y136F
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Cryptococcus neoformans strain; 5207
• 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.

Disease Class: Recurrent cryptococcosis [ICD-11: 1F27.0] [3]

• Resistant Disease: Recurrent cryptococcosis [ICD-11: 1F27.0]
• Resistant Drug: Fluconazole
• Molecule Alteration: Missense mutation; p.G484S (c.G1855T)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Cryptococcus neoformans stiain CN-5; 5207
• Experiment for Molecule Alteration: Genomic sequence assay
• Experiment for Drug Resistance: Microdilution and E-test methods assay
• Mechanism Description: A point mutation (G1855T) in the ERG11 gene was detected in the FCZ-resistant isolate (CN-5) only. And this mutation is responsible for the amino acid substitution glycine 484 for serine (G484S) in the ERG11 deduced protein sequence of C. neoformans.

Disease Class: Urinary tract infection [ICD-11: GC08.1] [5]

• Resistant Disease: Urinary tract infection [ICD-11: GC08.1]
• Resistant Drug: Fluconazole
• Molecule Alteration: Missense mutation; G42S
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Urinary Candida spp. Isolated; 5475
• Experiment for Molecule Alteration: RT-PCR; PCR; GeneSeq assay
• Experiment for Drug Resistance: Germ tube formation assay; Tween 80 opacity assay; MTP assay; Fluconazole susceptibility testing; Resistance modulation assay; Rhodamine efflux assay
• Mechanism Description: Fluconazole susceptibility testing of 34 urinary Candida isolates indicated that 76.5% were FLC-R, with a higher prevalence of resistance recorded in non-albicans Candida spp. (88.9%) than in Candida albicans (62.5%). The calculated Spearman's correlation coefficients implied significant positive correlations between fluconazole minimum inhibitory concentrations and both biofilm formation and phospholipase production. Real-time PCR results revealed that most FLC-R isolates (60%) significantly overexpressed at least one efflux pump gene, while 42.3% significantly upregulated the ERG11 gene. The most prevalent mutation detected upon ERG11 sequencing was G464S, which is conclusively linked to fluconazole resistance.

Disease Class: candidemia [ICD-11: MA15.1] [6]

• Resistant Disease: candidemia [ICD-11: MA15.1]
• Resistant Drug: Fluconazole
• Molecule Alteration: Mutation; G307A
• Experimental Note: Revealed Based on the Cell Line Data
• Experiment for Molecule Alteration: Genotyping assay
• Mechanism Description: The FLCR rate was 26.7% (91/341), out of which 75.8% (69/91) harboured the?ERG11Y132F?mutation. Patients infected with FLCR isolates had a higher mortality rate compared to their susceptible counterparts (49% for FLCR vs. 42% for susceptible). ECR rate was 2.1% (7/341) and isolates carried?FKS1F652L/R658G/W1370R?mutations. Concerningly, four ECR isolates were MDR. FLCR isolates grouped in distinct clusters without evidence of inter-hospital transmission, whereas large clusters containing susceptible isolates from all centres were noted.

Disease Class: candidemia [ICD-11: MA15.1] [6]

• Resistant Disease: candidemia [ICD-11: MA15.1]
• Resistant Drug: Fluconazole
• Molecule Alteration: Mutation; K444R/E+N450D
• Experimental Note: Revealed Based on the Cell Line Data
• Experiment for Molecule Alteration: Genotyping assay
• Mechanism Description: The FLCR rate was 26.7% (91/341), out of which 75.8% (69/91) harboured the?ERG11Y132F?mutation. Patients infected with FLCR isolates had a higher mortality rate compared to their susceptible counterparts (49% for FLCR vs. 42% for susceptible). ECR rate was 2.1% (7/341) and isolates carried?FKS1F652L/R658G/W1370R?mutations. Concerningly, four ECR isolates were MDR. FLCR isolates grouped in distinct clusters without evidence of inter-hospital transmission, whereas large clusters containing susceptible isolates from all centres were noted.

Disease Class: candidemia [ICD-11: MA15.1] [6]

• Resistant Disease: candidemia [ICD-11: MA15.1]
• Resistant Drug: Fluconazole
• Molecule Alteration: Mutation; W1370R
• Experimental Note: Revealed Based on the Cell Line Data
• Experiment for Molecule Alteration: Genotyping assay
• Mechanism Description: The FLCR rate was 26.7% (91/341), out of which 75.8% (69/91) harboured the?ERG11Y132F?mutation. Patients infected with FLCR isolates had a higher mortality rate compared to their susceptible counterparts (49% for FLCR vs. 42% for susceptible). ECR rate was 2.1% (7/341) and isolates carried?FKS1F652L/R658G/W1370R?mutations. Concerningly, four ECR isolates were MDR. FLCR isolates grouped in distinct clusters without evidence of inter-hospital transmission, whereas large clusters containing susceptible isolates from all centres were noted.

Flucytosine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Candida auris infection [ICD-11: 1F23.2] [7]

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

Isavuconazole

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Candida auris infection [ICD-11: 1F23.2] [2]

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

Disease Class: Candida auris infection [ICD-11: 1F23.2] [2]

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

Posaconazole

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Candida auris infection [ICD-11: 1F23.2] [2]

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

Disease Class: Candida auris infection [ICD-11: 1F23.2] [2]

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

Voriconazole

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Candida auris infection [ICD-11: 1F23.2] [2]

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

Disease Class: Candida auris infection [ICD-11: 1F23.2] [2]

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

References

• Ref 1: Simultaneous Emergence of Multidrug-Resistant Candida auris on 3 Continents Confirmed by Whole-Genome Sequencing and Epidemiological Analyses. Clin Infect Dis. 2017 Jan 15;64(2):134-140. doi: 10.1093/cid/ciw691. Epub 2016 Oct 20.
• Ref 2: A multicentre study of antifungal susceptibility patterns among 350 Candida auris isolates (2009-17) in India: role of the ERG11 and FKS1 genes in azole and echinocandin resistance. J Antimicrob Chemother. 2018 Apr 1;73(4):891-899. doi: 10.1093/jac/dkx480.
• Ref 3: G484S amino acid substitution in lanosterol 14-alpha demethylase (ERG11) is related to fluconazole resistance in a recurrent Cryptococcus neoformans clinical isolate. Antimicrob Agents Chemother. 2003 Nov;47(11):3653-6. doi: 10.1128/AAC.47.11.3653-3656.2003.
• Ref 4: 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 5: Elucidation of the mechanisms of fluconazole resistance and repurposing treatment options against urinary Candida spp. isolated from hospitalized patients in Alexandria, Egypt. BMC Microbiol. 2024 Oct 1;24(1):383.
• Ref 6: Multicentre Study of Candida parapsilosis Blood Isolates in Turkiye Highlights an Increasing Rate of Fluconazole Resistance and Emergence of Echinocandin and Multidrug Resistance. Mycoses. 2024 Nov;67(11):e70000.
• Ref 7: Genomic epidemiology of the UK outbreak of the emerging human fungal pathogen Candida auris. Emerg Microbes Infect. 2018 Mar 29;7(1):43. doi: 10.1038/s41426-018-0045-x.