Molecule Information

General Information of the Molecule (ID: Mol00886)

• Name: D-glucan-1,3-beta--UDP glucosyltransferase (FKS1) ,Aspergillus fumigatus
• Synonyms: FKS
• Molecule Type: Protein
• Gene Name: FKS
• Sequence:
  MSGYQQGGGHYNDGYGHQEHGDSFYQDEHGQAYYDHDYGDGYYDRSGYYGPDGNHNQQEG
  GYYDAGQPHDDYYGDHYYDQGNGQQGYDNRGRRRGDSEEDSETFSDFTMRSETARAADMD
  YYGRGDERYNSYADSQYGGRGYGYRPPSSQISYGANRSSGASTPVYGMDYGNALPAGQRS
  REPYPAWASDGQVPVSKEEIEDIFLDLVNKFGFQRDSMRNMYDHLMTMLDSRASRMTPNQ
  ALLSLHADYIGGDNANYRRWYFAAHLDLDDAVGFANMKLGKADRKTRKARKAAKKAAQQN
  PENVEETLEALEGDNSLEAAEYRWKTRMNKMSQHDRVRQLALFLLCWGEANQVRFLPECL
  CFIFKCADDYYNSPECQNRVEPVEEFTYLNEIITPLYQYCRDQGYEIVDGKYVRRERDHN
  QIIVSDMNQLFWYPEGIERIALEDKTRLVDIPPAERWTKLKDVVWKKAFFKTYKETRSWF
  HMITNFNRIWVIHLGAFWFFTAFNAQSLYTDNYQQQVNNKPPGYRIWSAVGFGGALSSFI
  QIAATICEWMYVPRRWAGAQHLTKRLMFLILVFVINLAPGVFVFAYSKSMGISKTIPLIV
  GIVHFFVALATFVFFSVMPLGGLFGSYLKKHGRQYVASQTFTASFPRLHGNDMWMSYGLW
  VCVFGAKLAESYFFLTLSFKDPIRILSPMQIHQCAGVKYIGNVLCHKQPQILLGLMFFMD
  LTLFFLDSYLWYIICNTVFSVARSFYLGVSIWSPWRNIFSRLPKRIYSKVLATTDMEIKY
  KPKVLISQVWNAIIISMYREHLLAIDHVQKLLYHQVPSEQEGKRTLRAPTFFVSQEDQSF
  KTEFFPPGSEAERRISFFAQSLSTPMPEPLPVDNMPTFTVLIPHYSEKILLSLREIIRED
  EPYSRVTLLEYLKQLHPHEWDCFVKDTKILADETSQFNGEPEKSEKDVAKSKIDDLPFYC
  IGFKSAAPEYTLRTRIWSSLRSQTLYRTVSGFMNYSRAIKLLYRVENPEVVQMFGGNSEK
  LERELERMARRKFKIVVSMQRYAKFNKEERENTEFLLRAYPDLQIAYLDEEPPVNEGEEP
  RLYSALIDGHCELLENGMRKPKFRIQLSGNPILGDGKSDNQNHSIIFYRGEYIQVIDANQ
  DNYLEECLKIRSVLAEFEELTTDNVSPYTPGIPSTNTNPVAILGAREYIFSENIGVLGDV
  AAGKEQTFGTLFARTLAQIGGKLHYGHPDFLNGIFMTTRGGISKAQKGLHLNEDIYAGMN
  AMIRGGRIKHCEYYQCGKGRDLGFGSILNFTTKIGTGMGEQMLSREYYYLGTQLPLDRFL
  SFYYAHPGFHINNMFIMLSVQMFMIVLINLGALKHETITCRYNPDLPITDPLRPTYCANL
  TPIVDWVNRCIISIFIVFFISFVPLAVQELTERGVWRMAMRLAKHFGSVSFMFEVFVCQI
  YANAVHQNLSFGGARYIGTGRGFATARIPFGVLYSRFAGPSIYAGARSLLMLLFATSTVW
  TAALIWFWVSLLALCISPFLFNPHQFAWNDFFIDYRDYLRWLSRGNSRSHASSWIGFCRL
  SRTRITGYKRKLLGVPSEKGSGDVPRARLTNIFFSEIIAPLVLVAVTLVPYLYINSRTGV
  RDNPETTDAILRLAIVAAGPIAINAGVAGVFFGMACCMGPIFSMCCKKFGAVLAAIAHAI
  AVIVLLAIFEVMFFLESWSWPRMLIGMIAAAAIQRFIYKLIIALALTREFKHDQSNIAWW
  TGKWYNMGWHSMSQPGREFLCKITELGYFSADFVLGHVLLFAMLPALCVPFIDKFHSVML
  FWLRPSRQIRPPIYSLKQSKLRKRRVIRFAILYFGMLILFLVLLIAPLVVRSMGLVKTPN
  LPFNLLQPLDKDNNDTMVTYTGNNIPAGFEPVESASSVATATS
• Uniprot ID: P87204_ASPFM

Kingdom: Fungi
Phylum: Ascomycota
Class: Eurotiomycetes
Order: Eurotiales
Family: Aspergillaceae
Genus: Aspergillus
Species: Aspergillus fumigatus

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) 3 drug(s) in total

Anidulafungin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Candida krusei infection [1]

• Resistant Disease: Candida krusei infection [ICD-11: 1F23.4]
• Resistant Drug: Anidulafungin
• Molecule Alteration: Missense mutation; p.F655C
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida krusei strain; 4909
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Broth macrodilution assay
• Mechanism Description: A Candida krusei strain from a patient with acute myelogenous leukemia that displayed reduced susceptibility to echinocandin drugs contained a heterozygous mutation, T2080k, in FkS1. The resulting Phe655-Cys substitution altered the sensitivity of glucan synthase to echinocandin drugs, consistent with a common mechanism for echinocandin resistance in Candida spp.

Caspofungin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Candida krusei infection [2]

• Resistant Disease: Candida krusei infection [ICD-11: 1F23.4]
• Resistant Drug: Caspofungin
• Molecule Alteration: Missense mutation; p.R1361G
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida krusei strain; 4909
• In Vivo Model: CD-1 murine model of disseminated candidiasis; Mus musculus
• Experiment for Molecule Alteration: Site-directed mutagenesis; MLST assay
• Experiment for Drug Resistance: Liquid broth microdilution assay
• Mechanism Description: One group of amino acid substitutions, in the Fks proteins of S. cerevisiae (F639I, V641k, D646Y) and C. albicans (S645F, S645P, S645Y), maps to a short conserved region of ScFks1p and CaFks1p, which lead to caspofungin resistance in the S. cerevisiae and C. albicans as well as C.krusei.

Disease Class: Candida krusei infection [1]

• Resistant Disease: Candida krusei infection [ICD-11: 1F23.4]
• Resistant Drug: Caspofungin
• Molecule Alteration: Missense mutation; p.F655C
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida krusei strain; 4909
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Broth macrodilution assay
• Mechanism Description: A Candida krusei strain from a patient with acute myelogenous leukemia that displayed reduced susceptibility to echinocandin drugs contained a heterozygous mutation, T2080k, in FkS1. The resulting Phe655-Cys substitution altered the sensitivity of glucan synthase to echinocandin drugs, consistent with a common mechanism for echinocandin resistance in Candida spp.

Micafungin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Candida krusei infection [1]

• Resistant Disease: Candida krusei infection [ICD-11: 1F23.4]
• Resistant Drug: Micafungin
• Molecule Alteration: Missense mutation; p.F655C
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida krusei strain; 4909
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Broth macrodilution assay
• Mechanism Description: A Candida krusei strain from a patient with acute myelogenous leukemia that displayed reduced susceptibility to echinocandin drugs contained a heterozygous mutation, T2080k, in FkS1. The resulting Phe655-Cys substitution altered the sensitivity of glucan synthase to echinocandin drugs, consistent with a common mechanism for echinocandin resistance in Candida spp.

Disease Class: Chronic pulmonary aspergillosis [3]

• Resistant Disease: Chronic pulmonary aspergillosis [ICD-11: 1F20.5]
• Resistant Drug: Micafungin
• Molecule Alteration: Missense mutation; p.F641S
• 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: Emergence of Echinocandin resistance due to a point mutation (F641S ) in the fks1 gene of Aspergillus fumigatus in a patient with chronic pulmonary aspergillosis.

Disease Class: Chronic pulmonary aspergillosis [3]

• Resistant Disease: Chronic pulmonary aspergillosis [ICD-11: 1F20.5]
• Resistant Drug: Micafungin
• Molecule Alteration: Missense mutation; p.F675S
• 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: Emergence of Echinocandin resistance due to a point mutation (F675S ) in the fks1 gene of Aspergillus fumigatus in a patient with chronic pulmonary aspergillosis.

References

• Ref 1: Acquired echinocandin resistance in a Candida krusei isolate due to modification of glucan synthase. Antimicrob Agents Chemother. 2007 May;51(5):1876-8. doi: 10.1128/AAC.00067-07. Epub 2007 Feb 26.
• Ref 2: Specific substitutions in the echinocandin target Fks1p account for reduced susceptibility of rare laboratory and clinical Candida sp. isolates. Antimicrob Agents Chemother. 2005 Aug;49(8):3264-73. doi: 10.1128/AAC.49.8.3264-3273.2005.
• Ref 3: Emergence of Echinocandin Resistance Due to a Point Mutation in the fks1 Gene of Aspergillus fumigatus in a Patient with Chronic Pulmonary Aspergillosis. Antimicrob Agents Chemother. 2017 Nov 22;61(12):e01277-17. doi: 10.1128/AAC.01277-17. Print 2017 Dec.