Basis of narrow-spectrum activity of fidaxomicin on Clostridioides difficile

  • Nature. 2022 Apr;604(7906):541-545. doi: 10.1038/s41586-022-04545-z.
Xinyun Cao   #  1 ,  Hande Boyaci   #  2 ,  James Chen  2 ,  Yu Bao  1 ,  Robert Landick  3  4 ,  Elizabeth A Campbell  5
Affiliations
  • 1. Department of Biochemistry, University of Wisconsin-Madison, Madison, WI, United States.
  • 2. Laboratory of Molecular Biophysics, The Rockefeller University, New York, NY, United States.
  • 3. Department of Biochemistry, University of Wisconsin-Madison, Madison, WI, United States. [email protected].
  • 4. Department of Bacteriology, University of Wisconsin-Madison, Madison, WI, United States. [email protected].
  • 5. Laboratory of Molecular Biophysics, The Rockefeller University, New York, NY, United States. [email protected].
  • # Contributed equally.
PMID: 35388215 DOI: 10.1038/s41586-022-04545-z
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.

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