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 [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 [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 [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 [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 [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 [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 [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 [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.

Flucytosine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Candida auris infection [5]

• 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 [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 [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 [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 [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 [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 [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: 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.