Journal
NATURE
Volume 604, Issue 7906, Pages 541-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41586-022-04545-z
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Funding
- Simons Foundation [SF349247]
- NYSTAR
- NIH [GM38660, GM114450]
- Revson Foundation [CEN5650030]
- Agouron Institute [F00316]
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Fidaxomicin is effective in treating Cdiff infections with minimal impact on gut commensals, and its activity is determined by a specific binding determinant in Cdiff RNA polymerase.
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. Cdiffinfections are a leading cause of nosocomial deaths(1). Fidaxomicin, which inhibits RNA polymerase, targets Cdiff with minimal effects on gut commensals, reducing recurrence of Cdiffinfection(2,3). Here we present the cryo-electron microscopy structure of CdeRNA 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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