Drug Information

Drug (ID: DG00012) and It's Reported Resistant Information

• Name: Caspofungin
• Synonyms: CASPO; Cancidas; Capsofungin; Caspofungin [INN]; M991; Cancidas (TM); Cancidas (TN); Caspofungin (INN); MK-0991; L-743,872; [1(R)-hydroxyethyl]-1,4,7,13,16,22-hexaazatricyclo[22.3.0.0(9,13)]heptacosane-2,5,8,14,17,23-hexaone diacetate; Pneumocandin B0, 1-[(4R,5S)-5-[(2-aminoethyl)amino]-N2-(10,12-dimethyl-1-oxotetradecyl)-4-hydroxy-L-ornithine]-5-[(3R)-3-hydroxy-L-ornithine]-(9CI); (4R,5S)-5-((2-Aminoethyl)amino)-N(sup 2)-(10,12-dimethyltetradecanoyl)-4-hydroxy-L-ornithyl-L-threonyl-trans-4-hydroxy-L-prolyl-(S)-4-hydroxy-4-(p-hydroxyphenyl)-L-threonyl-threo-3-hydroxy-L-ornithyl-trans-3-hydroxy-L-proline cyclic (6-1)-peptide; (4R,5S)-5-((2-aminoethyl)amino)-N(2)-(10,12-dimethyltetradecanoyl)-4-hydroxy-L-ornithyl-L-threonyl-trans-4-hydroxy-L-prolyl-(S)-4-hydroxy-4-(p-hydroxyphenyl)-L-threonyl-threo-3-hydroxy-L-ornithyl-trans-3-hydroxy-L-proline cyclic (6-1)-peptide; 1-[(4R,5S)-5-[(2-aminoethyl)amino]-N(2)-(10,12-dimethyl-1-oxotetradecyl)-4-hydroxy-L-ornithine]-5-[(3R)-3-hydroxy-L-ornithine]-pneumocandin B0
• Indication:
  In total 1 Indication(s)
  Fungal infection [ICD-11: 1F29-1F2F]; Approved; [1]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (2 diseases)
  Candidosis [ICD-11: 1F23]; [1]
  Fungal infection [ICD-11: 1F29-1F2F]; [1]
• Target: Fungal 1,3-beta-glucan synthase (Fung GSC2); FKS2_YEAST; [1]
• Formula: C52H88N10O15
• IsoSMILES: CCC(C)CC(C)CCCCCCCCC(=O)N[C@H]1C[C@H]([C@H](NC(=O)[C@@H]2[C@H](CCN2C(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@@H]3C[C@H](CN3C(=O)[C@@H](NC1=O)[C@@H](C)O)O)[C@@H]([C@H](C4=CC=C(C=C4)O)O)O)[C@@H](CCN)O)O)NCCN)O
• InChI: 1S/C52H88N10O15/c1-5-28(2)24-29(3)12-10-8-6-7-9-11-13-39(69)56-34-26-38(68)46(55-22-21-54)60-50(75)43-37(67)19-23-61(43)52(77)41(36(66)18-20-53)58-49(74)42(45(71)44(70)31-14-16-32(64)17-15-31)59-48(73)35-25-33(65)27-62(35)51(76)40(30(4)63)57-47(34)72/h14-17,28-30,33-38,40-46,55,63-68,70-71H,5-13,18-27,53-54H2,1-4H3,(H,56,69)(H,57,72)(H,58,74)(H,59,73)(H,60,75)/t28 ,29 ,30-,33-,34+,35+,36-,37+,38-,40+,41+,42+,43+,44+,45+,46+/m1/s1
• InChIKey: JYIKNQVWKBUSNH-OGZDCFRISA-N
• PubChem CID: 2826718
• ChEBI ID: CHEBI:474180
• TTD Drug ID: D00ZCN
• VARIDT ID: DR00493
• DrugBank ID: DB00520

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

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.S645Y
• Resistant Disease: Candida albicans infection [ICD-11: 1F23.Y]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida tropicalis strain NR3; 5482
• In Vivo Model: DBA/2J murine model of disseminated candidiasis; DBA/2N 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.

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

• Molecule Alteration: Missense mutation; p.S645F
• Resistant Disease: Candida albicans infection [ICD-11: 1F23.Y]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain; 5476
• In Vivo Model: DBA/2J murine model of disseminated candidiasis; DBA/2N 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.

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

• Molecule Alteration: Missense mutation; p.S645P
• Resistant Disease: Candida albicans infection [ICD-11: 1F23.Y]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Candida albicans strain; 5476
• Experiment for Molecule Alteration: NGS sequencing assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Amino acid changes in FkS1 may contribute to Candida albicans emerging caspofungin resistance.

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

• 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: 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).

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: Missense 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) [1]

• Molecule Alteration: Missense mutation; p.R1361G
• Resistant Disease: Candida krusei infection [ICD-11: 1F23.4]
• 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.

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

• 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) [8]

• 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.

Fungal infection [ICD-11: 1F29-1F2F]

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.F639I
• Resistant Disease: Saccharomyces cerevisiae infection [ICD-11: 1F29-1F2F]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Saccharomyces cerevisiae strain; 4932
• 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.

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

• Molecule Alteration: Missense mutation; p.V641K
• Resistant Disease: Saccharomyces cerevisiae infection [ICD-11: 1F29-1F2F]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Saccharomyces cerevisiae strain; 4932
• 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.

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

• Molecule Alteration: Missense mutation; p.D646Y
• Resistant Disease: Saccharomyces cerevisiae infection [ICD-11: 1F29-1F2F]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Saccharomyces cerevisiae strain; 4932
• 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.

References

• Ref 1: 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 2: Assessing resistance to the echinocandin antifungal drug caspofungin in Candida albicans by profiling mutations in FKS1. Antimicrob Agents Chemother. 2006 Jun;50(6):2058-63. doi: 10.1128/AAC.01653-05.
• Ref 3: 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 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: 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 8: 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.