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bioRxiv · 10.1101/2022.01.17.476619

Basis of narrow-spectrum activity of fidaxomicin on gut pathogen Clostridioides difficile

Cao, X.·Boyaci, H.·Chen, J.·Bao, Y.·Landick, R.·Campbell, E. A.
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Abstract

Fidaxomicin (Fdx) is widely used to treat Clostridioides difficile (Cdiff) infections (CDIs), but the molecular basis of its narrow-spectrum activity in the human gut microbiome remains enigmatic. CDIs are a leading cause of nosocomial deaths. Fdx, which inhibits RNA polymerase (RNAP), targets Cdiff with minimal effects on gut commensals, reducing CDI recurrence. Here, we present the cryo-electron microscopy structure of Cdiff RNAP in complex with Fdx, allowing us to identify a crucial Fdx-binding determinant of Cdiff RNAP that is absent in most gut microbiota like Proteobacteria and Bacteroidetes. By combining structural, biochemical, and bioinformatic analyses, we establish that a single RNAP residue is a sensitizing element for Fdx narrow-spectrum activity. Our results provide a blueprint for targeted drug design against an important human pathogen.

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Cao, X., Boyaci, H., Chen, J., Bao, Y., Landick, R., Campbell, E. A.. 2022-01-17. Basis of narrow-spectrum activity of fidaxomicin on gut pathogen Clostridioides difficile. https://doi.org/10.1101/2022.01.17.476619

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