Drug Information

Drug (ID: DG00079) and It's Reported Resistant Information

• Name: Micafungin
• Synonyms: Mycamine; FK463; FK-463; Mycamine (TN); Mycamine(TM)
• Indication:
  In total 1 Indication(s)
  Candidosis [ICD-11: 1F23]; Approved; [1]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (2 diseases)
  Aspergillosis [ICD-11: 1F20]; [2]
  Candidosis [ICD-11: 1F23]; [3]
• Target: Fungal 1,3-beta-glucan synthase (Fung GSC2); FKS2_YEAST; [1]
• Formula: C56H71N9O23S
• IsoSMILES: CCCCCOC1=CC=C(C=C1)C2=CC(=NO2)C3=CC=C(C=C3)C(=O)N[C@H]4C[C@H]([C@H](NC(=O)[C@@H]5[C@H]([C@H](CN5C(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@@H]6C[C@H](CN6C(=O)[C@@H](NC4=O)[C@@H](C)O)O)[C@@H]([C@H](C7=CC(=C(C=C7)O)OS(=O)(=O)O)O)O)[C@@H](CC(=O)N)O)C)O)O)O
• InChI: 1S/C56H71N9O23S/c1-4-5-6-17-86-32-14-11-28(12-15-32)39-21-33(63-87-39)27-7-9-29(10-8-27)49(75)58-34-20-38(70)52(78)62-54(80)45-46(72)25(2)23-65(45)56(82)43(37(69)22-41(57)71)60-53(79)44(48(74)47(73)30-13-16-36(68)40(18-30)88-89(83,84)85)61-51(77)35-19-31(67)24-64(35)55(81)42(26(3)66)59-50(34)76/h7-16,18,21,25-26,31,34-35,37-38,42-48,52,66-70,72-74,78H,4-6,17,19-20,22-24H2,1-3H3,(H2,57,71)(H,58,75)(H,59,76)(H,60,79)(H,61,77)(H,62,80)(H,83,84,85)/t25-,26+,31+,34-,35-,37+,38+,42-,43-,44-,45-,46-,47-,48-,52+/m0/s1
• InChIKey: PIEUQSKUWLMALL-YABMTYFHSA-N
• PubChem CID: 477468
• ChEBI ID: CHEBI:600520
• TTD Drug ID: D06TOE
• INTEDE ID: DR1083
• DrugBank ID: DB01141

Type(s) of Resistant Mechanism of This Drug

  ADTT: Aberration of the Drug's Therapeutic Target

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: D-glucan-1,3-beta--UDP glucosyltransferase (FKS1) [2]

• Molecule Alteration: Missense mutation; p.F641S
• Resistant Disease: Chronic pulmonary aspergillosis [ICD-11: 1F20.5]
• 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.

Key Molecule: D-glucan-1,3-beta--UDP glucosyltransferase (FKS1) [2]

• Molecule Alteration: Missense mutation; p.F675S
• Resistant Disease: Chronic pulmonary aspergillosis [ICD-11: 1F20.5]
• 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.

Candidosis [ICD-11: 1F23]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: D-glucan-1,3-beta--UDP glucosyltransferase (FKS1) [1]

• Molecule Alteration: Missense mutation; p.S639P
• 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: 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).

Key Molecule: D-glucan-1,3-beta--UDP glucosyltransferase (FKS1) [4]

• Molecule Alteration: Missense mutation; p.S639F
• 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: Echinocandin (micafungin, caspofungin, and anidulafungin) resistance was linked to a novel mutation S639F in FkS1 hot spot region I.

Key Molecule: D-glucan-1,3-beta--UDP glucosyltransferase (FKS1) [5]

• Molecule Alteration: Missense mutation; p.S652Y
• 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: 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.

Key Molecule: D-glucan-1,3-beta--UDP glucosyltransferase (FKS1) [6]

• Molecule Alteration: Missense mutation; p.D632G (c.A1895G)
• Resistant Disease: Candida glabrata infection [ICD-11: 1F23.3]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida glabrata strain; 5478
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: NCCLS method M-27A with broth macrodilution techniques assay
• Mechanism Description: Fks1p and Fks2p amino acid substitutions confer reduced echinocandin susceptibility in C. glabrata.

Key Molecule: D-glucan-1,3-beta--UDP glucosyltransferase (FKS1) [6]

• Molecule Alteration: Missense mutation; p.D632E (c.T1896G)
• Resistant Disease: Candida glabrata infection [ICD-11: 1F23.3]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida glabrata strain; 5478
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: NCCLS method M-27A with broth macrodilution techniques assay
• Mechanism Description: Recently, three reports showed that amino acid substitutions in Fks1p (D632E) and Fks2p (F659V) are responsible for clinical echinocandin resistance in C. glabrata.

Key Molecule: D-glucan-1,3-beta--UDP glucosyltransferase (FKS1) [6]

• Molecule Alteration: Missense mutation; p.D632Y (c.G1894T)
• Resistant Disease: Candida glabrata infection [ICD-11: 1F23.3]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida glabrata strain; 5478
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: NCCLS method M-27A with broth macrodilution techniques assay
• Mechanism Description: Fks1p and Fks2p amino acid substitutions confer reduced echinocandin susceptibility in C. glabrata.

Key Molecule: D-glucan-1,3-beta--UDP glucosyltransferase (FKS1) [6]

• Molecule Alteration: Missense mutation; p.F625S (c.T1874C)
• Resistant Disease: Candida glabrata infection [ICD-11: 1F23.3]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida glabrata strain; 5478
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: NCCLS method M-27A with broth macrodilution techniques assay
• Mechanism Description: Fks1p and Fks2p amino acid substitutions confer reduced echinocandin susceptibility in C. glabrata.

Key Molecule: D-glucan-1,3-beta--UDP glucosyltransferase (FKS1) [6]

• Molecule Alteration: Missense mutation; p.S629P (c.T1885C)
• Resistant Disease: Candida glabrata infection [ICD-11: 1F23.3]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida glabrata strain; 5478
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: NCCLS method M-27A with broth macrodilution techniques assay
• Mechanism Description: Fks1p and Fks2p amino acid substitutions confer reduced echinocandin susceptibility in C. glabrata.

Key Molecule: D-glucan-1,3-beta--UDP glucosyltransferase (FKS1) [6]

• Molecule Alteration: Missense mutation; p.F659V (c.T1975G)
• Resistant Disease: Candida glabrata infection [ICD-11: 1F23.3]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida glabrata strain; 5478
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: NCCLS method M-27A with broth macrodilution techniques assay
• Mechanism Description: Recently, three reports showed that amino acid substitutions in Fks1p (D632E) and Fks2p (F659V) are responsible for clinical echinocandin resistance in C. glabrata.

Key Molecule: D-glucan-1,3-beta--UDP glucosyltransferase (FKS1) [6]

• Molecule Alteration: Missense mutation; p.F659S (c.T1976C)
• Resistant Disease: Candida glabrata infection [ICD-11: 1F23.3]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida glabrata strain; 5478
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: NCCLS method M-27A with broth macrodilution techniques assay
• Mechanism Description: Fks1p and Fks2p amino acid substitutions confer reduced echinocandin susceptibility in C. glabrata.

Key Molecule: D-glucan-1,3-beta--UDP glucosyltransferase (FKS1) [6]

• Molecule Alteration: Frameshift mutation; p.F659del (c.1974-CTT-1976)
• Resistant Disease: Candida glabrata infection [ICD-11: 1F23.3]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida glabrata strain; 5478
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: NCCLS method M-27A with broth macrodilution techniques assay
• Mechanism Description: Fks1p and Fks2p amino acid substitutions confer reduced echinocandin susceptibility in C. glabrata.

Key Molecule: D-glucan-1,3-beta--UDP glucosyltransferase (FKS1) [6]

• Molecule Alteration: Nonsense mutation; p.R1377STOP (c.A4129T)
• Resistant Disease: Candida glabrata infection [ICD-11: 1F23.3]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida glabrata strain; 5478
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: NCCLS method M-27A with broth macrodilution techniques assay
• Mechanism Description: Fks1p and Fks2p amino acid substitutions confer reduced echinocandin susceptibility in C. glabrata.

Key Molecule: D-glucan-1,3-beta--UDP glucosyltransferase (FKS1) [3]

• Molecule Alteration: Missense mutation; p.F655C
• Resistant Disease: Candida krusei infection [ICD-11: 1F23.4]
• 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.

Key Molecule: D-glucan-1,3-beta--UDP glucosyltransferase (FKS1) [7]

• Molecule Alteration: Missense mutation; p.P660A
• Resistant Disease: Invasive candidiasis [ICD-11: 1F23.5]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida parapsilosis strain; 5480
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: M27-A2 broth dilution method assay
• Mechanism Description: Overall, these data firmly indicate that a naturally occurring P660A substitution in Fks1p from the C. parapsilosis group accounts for the reduced susceptibility 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: 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.
• Ref 3: 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 4: 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 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.
• Ref 6: Effect of Candida glabrata FKS1 and FKS2 mutations on echinocandin sensitivity and kinetics of 1,3-beta-D-glucan synthase: implication for the existing susceptibility breakpoint. Antimicrob Agents Chemother. 2009 Sep;53(9):3690-9. doi: 10.1128/AAC.00443-09. Epub 2009 Jun 22.
• Ref 7: A naturally occurring proline-to-alanine amino acid change in Fks1p in Candida parapsilosis, Candida orthopsilosis, and Candida metapsilosis accounts for reduced echinocandin susceptibility. Antimicrob Agents Chemother. 2008 Jul;52(7):2305-12. doi: 10.1128/AAC.00262-08. Epub 2008 Apr 28.