Basis of narrow-spectrum activity of fidaxomicin on Clostridioides difficile

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.

Automated summary

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.