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Basis of narrow-spectrum activity of fidaxomicin on Clostridioides difficile

Author

Listed:
  • Xinyun Cao

    (University of Wisconsin–Madison)

  • Hande Boyaci

    (The Rockefeller University)

  • James Chen

    (The Rockefeller University)

  • Yu Bao

    (University of Wisconsin–Madison)

  • Robert Landick

    (University of Wisconsin–Madison
    University of Wisconsin–Madison)

  • Elizabeth A. Campbell

    (The Rockefeller University)

Abstract

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.

Suggested Citation

  • Xinyun Cao & Hande Boyaci & James Chen & Yu Bao & Robert Landick & Elizabeth A. Campbell, 2022. "Basis of narrow-spectrum activity of fidaxomicin on Clostridioides difficile," Nature, Nature, vol. 604(7906), pages 541-545, April.
    • Handle: RePEc:nat:nature:v:604:y:2022:i:7906:d:10.1038_s41586-022-04545-z
    DOI: 10.1038/s41586-022-04545-z
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