Basis of narrow-spectrum activity of fidaxomicin on Clostridioides difficile

Nature. 2022 Apr;604(7906):541-545. doi: 10.1038/s41586-022-04545-z. Epub 2022 Apr 6.


Fidaxomicin (Fdx) is widely used to treat Clostridioides difficile (Cdiff) infections, but the molecular basis of its narrow-spectrum activity in the human gut microbiome remains unknown. Cdiff infections are a leading cause of nosocomial deaths1. Fidaxomicin, which inhibits RNA polymerase, targets Cdiff with minimal effects on gut commensals, reducing recurrence of Cdiff infection2,3. Here we present the cryo-electron microscopy structure of Cdiff RNA polymerase in complex with fidaxomicin and identify a crucial fidaxomicin-binding determinant of Cdiff RNA polymerase that is absent in most gut microbiota such as Proteobacteria and Bacteroidetes. By combining structural, biochemical, genetic and bioinformatic analyses, we establish that a single residue in Cdiff RNA polymerase is a sensitizing element for fidaxomicin narrow-spectrum activity. Our results provide a blueprint for targeted drug design against an important human pathogen.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / pharmacology
  • Anti-Bacterial Agents / therapeutic use
  • Clostridioides
  • Clostridioides difficile*
  • Clostridium Infections* / drug therapy
  • Clostridium Infections* / microbiology
  • Cryoelectron Microscopy
  • DNA-Directed RNA Polymerases
  • Fidaxomicin / chemistry
  • Fidaxomicin / pharmacology
  • Fidaxomicin / therapeutic use
  • Humans


  • Anti-Bacterial Agents
  • DNA-Directed RNA Polymerases
  • Fidaxomicin