7L7B

Clostridioides difficile RNAP with fidaxomicin

Summary for 7L7B

• Entry DOI: 10.2210/pdb7l7b/pdb
• EMDB information: 23210
• Descriptor: DNA-directed RNA polymerase subunit alpha, DNA-directed RNA polymerase subunit beta, DNA-directed RNA polymerase subunit beta', ... (9 entities in total)
• Functional Keywords: fidaxomicin, clostridioides difficile rna polymerase, transcription, transcription-inhibitor complex, transcription/inhibitor
• Biological source: Clostridia bacterium; More
• Total number of polymer chains: 6
• Total formula weight: 398105.85

Authors

Boyaci, H.,Campbell, E.A.,Darst, S.A.,Chen, J. (deposition date: 2020-12-28, release date: 2022-02-02, Last modification date: 2025-05-21)

Primary citation

Cao, X.,Boyaci, H.,Chen, J.,Bao, Y.,Landick, R.,Campbell, E.A.
Basis of narrow-spectrum activity of fidaxomicin on Clostridioides difficile.
Nature, 604:541-545, 2022

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 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.

PubMed: 35388215
DOI: 10.1038/s41586-022-04545-z

Experimental method

ELECTRON MICROSCOPY (3.26 Å)