PT  - JOURNAL ARTICLE
AU  - Xinyun Cao
AU  - Hande Boyaci
AU  - James Chen
AU  - Yu Bao
AU  - Robert Landick
AU  - Elizabeth A. Campbell
TI  - Basis of narrow-spectrum activity of fidaxomicin on gut pathogen <em>Clostridioides difficile</em>
AID  - 10.1101/2022.01.17.476619
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.01.17.476619
4099  - http://biorxiv.org/content/early/2022/01/17/2022.01.17.476619.short
4100  - http://biorxiv.org/content/early/2022/01/17/2022.01.17.476619.full
AB  - 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.Competing Interest StatementThe authors have declared no competing interest.