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-Structure paper
Title | Basis of narrow-spectrum activity of fidaxomicin on Clostridioides difficile. |
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Journal, issue, pages | Nature, Vol. 604, Issue 7906, Page 541-545, Year 2022 |
Publish date | Apr 6, 2022 |
Authors | Xinyun Cao / Hande Boyaci / James Chen / Yu Bao / Robert Landick / Elizabeth A Campbell / |
PubMed 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 ...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 deaths. Fidaxomicin, which inhibits RNA polymerase, targets Cdiff with minimal effects on gut commensals, reducing recurrence of Cdiff infection. 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. |
External links | Nature / PubMed:35388215 / PubMed Central |
Methods | EM (single particle) |
Resolution | 3.26 Å |
Structure data | EMDB-23210, PDB-7l7b: |
Chemicals | ChemComp-ZN: ChemComp-MG: ChemComp-FI8: ChemComp-HOH: |
Source |
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Keywords | TRANSCRIPTION/INHIBITOR / fidaxomicin / Clostridioides difficile RNA polymerase / TRANSCRIPTION / TRANSCRIPTION-INHIBITOR complex |