Molecule Information

General Information of the Molecule (ID: Mol00892)

• Name: D-glucan-1,3-beta--UDP glucosyltransferase (FKS1) ,Candida auris
• Synonyms: FKS1; B9J08_000964; CA7LBN_002502; EC 2.4.1.34
• Molecule Type: Protein
• Gene Name: FKS1
• Sequence:
  MSYDNNHNYYDPNQQQGGQPGGEYYQQGAYDEMGQPVNYDQAGDYYDPNQQYQQQPYDMD
  GYQNYGQQGAAGYSADPEAFSDFSYGGGHAPGTPGYDQYGAQYTPSQMSYAGARSSGAST
  PIYGANPNYDPSQFQLSSNLPYPAWSADPQAPIKIEHIEDIFIDLTNKFGFQRDSMRNMF
  DYFMTLLDSRSSRMSPAQALLSLHADYIGGDNANYKKWFFASQQDLDESIGFANMNLGKI
  GRKARKASKKSKKARKAAEEHGQDIDALNNELEGDYSMEAANIRWKAKMNVLTPEERVRD
  IALYLLLWGEANQVRFTPELICFIFKTALDYLNSPQCQQRQEPVPEGDYLNRIITPIYRF
  IRSQVYEIYEGRFVKREKDHNKVIGYDDVNQLFWYPEGISRIIFNDGTRLVDIPMEERYM
  RLGEVEWQNIFFKTYKEVRTWLHLVTNFNRIWIIHVTIYWMYTAYNSPTLYTQDYVQTIN
  NRPTASSQWSAPAMGGMIASFIEVMATVFEWMFVPREWAGAQHLSRRLVFLIIILVINIV
  PFAYSFYWAGLSAISKSAHAVSIVGFFIAVATLLFFAIMPLGGLFTSYMNRRSRKYVASQ
  IFTANFHSLRGLDMWMSYLLWVTVFAAKLAESYFFLTLSLRDPIRNLSTMTMRCNGEQWF
  GDTLCKHQAKIVLGLMLLVDLFLFFLDTYMWYIICNCVFSIGRSFYLGISILTPWRNIFT
  RLPKRIYSKILATTEMEIKYKPKVLISQVWNAIVISMYREHLLAIDHVQKLLYHQVPSEI
  EGKRTLRAPTFFVSQDDNNFETEFFPRNSEAERRISFFAQSLATPILEPLPVDNMPTFTV
  FTPHYSEKILLSLREIIREDDQFSRVTLLEYLKQLHPVEWDCFVKDTKILAEETAAYENA
  DEEERSNEDGLKAKIDDLPFYCIGFKSAAPEYTLRTRIWASLRSQTLYRTVSGFMNYARA
  IKLLYRVENPELVQYFGGDPEGLELALEKMARRKFKFVVSMQRLAKFKEDEMENAEFLLR
  AYPDLQIAYLDEEPPLNEDEEPRVYSALIDGHCEVLDNGRRRPKFRVQLSGNPILGDGKS
  DNQNHAIIFHRGEYIQLIDANQDNYLEECLKIRSVLAEFEELNVEHVNPYAPGLKNNNDE
  KPAPVAILGAREYIFSENSGVLGDVAAGKEQTFGTLFARTLAQIGGKLHYGHPDFLNATF
  MLTRGGVSKAQKGLHLNEDIYAGMTAMLRGGRIKHCEYYQCGKGRDMGFGSICNFTTKIG
  AGMGEQMLSREYYYLSTQLPLDRFLSFYYGHPGFHINNLFIQLSLQTFMLVLANLNSLAH
  ESILCDYDRNVPITDPLRPFGCYNLSPAIDWIRRYTLSIFIVFWISFIPLVVQELIERGL
  WKATQRFFRHFISLSPMFEVFLAQIYSNSLFTDLTVGGARYISTGRGFATSRIPFSILFS
  RFADSAIYMGSRSMLILLFGSVAHWQAPLLWFWASLSALMFSPFLFNPHQFAWEDFFIDY
  RDFIRWLSRGNTKWHRNSWIGYIKLSRSRVTGFKRKLTGDISEKSAGDASRAHRSNVFMA
  DFLPCLFYAAGLFVAYTYVNAQTGVTRWSVDGRDSTEPIKVNSVVRIVICALAPVVIDIG
  CLGVCLGMACCAGPMLGLCCKKTGAVIAGVAHGVAVIVHLVFFIVMWVLEGFNFARMLLG
  IVTMIYIQRVLFKILTLLFLTREFKNDKSNTAFWTGKWYNTGMGYMAATQPAREFVAKII
  EMSEFAGDFILAHLILFIQLPILCIPLIDRWHSTMLFWLKPSRLIRPPIYSLKQAKLRKR
  IVRKYCTLYFAILVLFIVIIAAPAVAGRFIADNLGANMSGTFEGLFQPRKVKNNDTGKVS
  SWWSTSDVKITFWSFTPTTSNVYTTKAF
• Uniprot ID: A0A2H1A4W2_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

Drug Resistance Data Categorized by Drug

Approved Drug(s) 4 drug(s) in total

Anidulafungin

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

Disease Class: Candida auris infection [2]

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

Disease Class: Candida auris infection [3]

• Resistant Disease: Candida auris infection [ICD-11: 1F23.2]
• Resistant Drug: Anidulafungin
• Molecule Alteration: Missense mutation; p.S652Y
• 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.

Caspofungin

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

Disease Class: Candida auris infection [2]

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

Disease Class: Candida auris infection [3]

• Resistant Disease: Candida auris infection [ICD-11: 1F23.2]
• Resistant Drug: Caspofungin
• Molecule Alteration: Missense mutation; p.S652Y
• 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.

Micafungin

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

Disease Class: Candida auris infection [2]

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

Disease Class: Candida auris infection [3]

• Resistant Disease: Candida auris infection [ICD-11: 1F23.2]
• Resistant Drug: Micafungin
• Molecule Alteration: Missense mutation; p.S652Y
• 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.

Rezafungin

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

Investigative Drug(s) 1 drug(s) in total

Echinocandins

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Recurrent oropharyngeal candidiasis [4]

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

References

• Ref 1: Activity of CD101, a long-acting echinocandin, against clinical isolates of Candida auris. Diagn Microbiol Infect Dis. 2018 Mar;90(3):196-197. doi: 10.1016/j.diagmicrobio.2017.10.021. Epub 2017 Nov 7.
• Ref 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: Genomic epidemiology of the UK outbreak of the emerging human fungal pathogen Candida auris. Emerg Microbes Infect. 2018 Mar 29;7(1):43. doi: 10.1038/s41426-018-0045-x.
• Ref 4: Antifungal Drug Resistance: Molecular Mechanisms in Candida albicans and Beyond .Chem Rev. 2021 Mar 24;121(6):3390-3411. doi: 10.1021/acs.chemrev.0c00199. Epub 2020 May 22. 10.1021/acs.chemrev.0c00199