Drug Information

Drug (ID: DG00076) and It's Reported Resistant Information

• Name: Fidaxomicin
• Synonyms: Dificid (TN)
• Indication:
  In total 1 Indication(s)
  Clostridium difficile enterocolitis [ICD-11: 1A04]; Approved; [1]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (1 diseases)
  Bacterial infection [ICD-11: 1A00-1C4Z]; [1]
  Disease(s) with Resistance Information Validated by in-vivo Model for This Drug (1 diseases)
  Clostridioides difficile intestinal infection [ICD-11: 1A04]; [2]
• Target: Bacterial RNA polymerase switch region (Bact RNAP-SR); NOUNIPROTAC; [1]
• Formula: C52H74Cl2O18
• IsoSMILES: CC[C@H]1/C=C(/[C@H](C/C=C/C=C(/C(=O)O[C@@H](C/C=C(/C=C(/[C@@H]1O[C@H]2[C@H]([C@H]([C@@H](C(O2)(C)C)OC(=O)C(C)C)O)O)\\C)\\C)[C@@H](C)O)\\CO[C@H]3[C@H]([C@H]([C@@H]([C@H](O3)C)OC(=O)C4=C(C(=C(C(=C4O)Cl)O)Cl)CC)O)OC)O)\\C
• InChI: 1S/C52H74Cl2O18/c1-13-30-22-26(6)33(56)18-16-15-17-31(23-66-51-45(65-12)42(61)44(29(9)67-51)69-49(64)35-32(14-2)36(53)39(58)37(54)38(35)57)48(63)68-34(28(8)55)20-19-25(5)21-27(7)43(30)70-50-41(60)40(59)46(52(10,11)72-50)71-47(62)24(3)4/h15-17,19,21-22,24,28-30,33-34,40-46,50-51,55-61H,13-14,18,20,23H2,1-12H3/b16-15+,25-19+,26-22+,27-21+,31-17+/t28-,29-,30+,33+,34+,40-,41+,42+,43+,44-,45+,46+,50-,51-/m1/s1
• InChIKey: ZVGNESXIJDCBKN-UUEYKCAUSA-N
• PubChem CID: 10034073
• TTD Drug ID: D06LNW
• VARIDT ID: DR00545
• DrugBank ID: DB08874

Type(s) of Resistant Mechanism of This Drug

  ADTT: Aberration of the Drug's Therapeutic Target

  EADR: Epigenetic Alteration of DNA, RNA or Protein

Drug Resistance Data Categorized by Their Corresponding Diseases

ICD-01: Infectious/parasitic diseases

Bacterial infection [ICD-11: 1A00-1C4Z]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: DNA-directed RNA polymerase subunit beta' (RPOC) [1]

• Molecule Alteration: Missense mutation; p.D244Y
• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Clostridioides difficile ATCC 43255; 499175
• In Vitro Model: Clostridioides difficile NB95009; 1496
• In Vitro Model: Clostridioides difficile NB95026; 1496
• In Vitro Model: Clostridioides difficile NB95031; 1496
• In Vitro Model: Clostridioides difficile NB95047; 1496
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: NB95026-JAL0865 had a single mutation encoding a D244Y substitution in the RNA polymerase subunit Beta.Reduced susceptibility to fidaxomicin and vancomycin was associated with mutations mediating target modifications (RNA polymerase and cell wall, respectively), as well as with mutations that may contribute to reduced susceptibility via other mechanisms.

Clostridioides difficile intestinal infection [ICD-11: 1A04]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: DNA-directed RNA polymerase subunit beta (RPOB) [2]

• Molecule Alteration: Mutation; p.E1073K+p.Q1074K+p.V1143F
• Resistant Disease: Clostridium difficile infection [ICD-11: 1A04.0]
• Experimental Note: Discovered Using In-vivo Testing Model
• Mechanism Description: Despite both drugs share a common target, the nucleotide substitution within rpoB of fidaxomicin and RIF-resistant strains locate differently. In vitro study has revealed that amino acid substitutions in either rpoB at E1073K, Q1074K and V1143F or rpoC at D273Y confer resistance to fidaxomicin.

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: DNA-directed RNA polymerase subunit beta' (RPOC) [2]

• Molecule Alteration: Missense mutation; p.D273Y
• Resistant Disease: Clostridium difficile infection [ICD-11: 1A04.0]
• Experimental Note: Discovered Using In-vivo Testing Model
• Mechanism Description: Despite both drugs share a common target, the nucleotide substitution within rpoB of fidaxomicin and RIF-resistant strains locate differently. In vitro study has revealed that amino acid substitutions in either rpoB at E1073K, Q1074K and V1143F or rpoC at D273Y confer resistance to fidaxomicin.

References

• Ref 1: In vitro selection, via serial passage, of Clostridium difficile mutants with reduced susceptibility to fidaxomicin or vancomycin. J Antimicrob Chemother. 2014 Jan;69(1):41-4. doi: 10.1093/jac/dkt302. Epub 2013 Jul 25.
• Ref 2: Insights into drug resistance mechanisms in Clostridium difficile .Essays Biochem. 2017 Mar 3;61(1):81-88. doi: 10.1042/EBC20160062. Print 2017 Feb 28. 10.1042/EBC20160062