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Basis of narrow-spectrum activity of fidaxomicin on Clostridioides difficile
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Basis of narrow-spectrum activity of fidaxomicin on Clostridioides difficile
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Journal Article
Basis of narrow-spectrum activity of fidaxomicin on Clostridioides difficile
2022
Overview
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
1
. Fidaxomicin, which inhibits RNA polymerase, targets
Cdiff
with minimal effects on gut commensals, reducing recurrence of
Cdiff
infection
2
,
3
. 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.
Structural analysis of
Clostridioides difficile
RNA polymerase in complex with fidaxomicin combined with biochemical, genetic and bioinformatic analyses identifies a key residue that determines fidaxomicin sensitivity.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ 38/70
/ 82
/ 82/16
/ 82/80
/ 82/83
/ Anti-Bacterial Agents - pharmacology
/ Anti-Bacterial Agents - therapeutic use
/ Clostridium Infections - drug therapy
/ Clostridium Infections - microbiology
/ DNA-Directed RNA Polymerases
/ E coli
/ Enzymes
/ Fidaxomicin - therapeutic use
/ Humanities and Social Sciences
/ Humans
/ Science
