Basis of narrow-spectrum activity of fidaxomicin on Clostridioides difficile

Xinyun Cao, Hande Boyaci, James Chen, Yu Bao, Robert Landick () and Elizabeth A. Campbell ()
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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
Elizabeth A. Campbell: The Rockefeller University

Nature, 2022, vol. 604, issue 7906, 541-545

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41586-022-04545-z

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