Potent and specific antibiotic combination therapy against Clostridioides difficile.
Journal
Nature chemical biology
ISSN: 1552-4469
Titre abrégé: Nat Chem Biol
Pays: United States
ID NLM: 101231976
Informations de publication
Date de publication:
Jul 2024
Jul 2024
Historique:
received:
05
01
2023
accepted:
15
05
2024
medline:
29
6
2024
pubmed:
29
6
2024
entrez:
28
6
2024
Statut:
ppublish
Résumé
Keratinicyclins and keratinimicins are recently discovered glycopeptide antibiotics. Keratinimicins show broad-spectrum activity against Gram-positive bacteria, while keratinicyclins form a new chemotype by virtue of an unusual oxazolidinone moiety and exhibit specific antibiosis against Clostridioides difficile. Here we report the mechanism of action of keratinicyclin B (KCB). We find that steric constraints preclude KCB from binding peptidoglycan termini. Instead, KCB inhibits C. difficile growth by binding wall teichoic acids (WTAs) and interfering with cell wall remodeling. A computational model, guided by biochemical studies, provides an image of the interaction of KCB with C. difficile WTAs and shows that the same H-bonding framework used by glycopeptide antibiotics to bind peptidoglycan termini is used by KCB for interacting with WTAs. Analysis of KCB in combination with vancomycin (VAN) shows highly synergistic and specific antimicrobial activity, and that nanomolar combinations of the two drugs are sufficient for complete growth inhibition of C. difficile, while leaving common commensal strains unaffected.
Identifiants
pubmed: 38942968
doi: 10.1038/s41589-024-01651-z
pii: 10.1038/s41589-024-01651-z
doi:
Substances chimiques
Anti-Bacterial Agents
0
Vancomycin
6Q205EH1VU
Teichoic Acids
0
Peptidoglycan
0
CB-183,315
0
Peptides, Cyclic
0
Lipopeptides
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
924-933Subventions
Organisme : Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.)
ID : 1R01GM129496
Organisme : Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.)
ID : 1R35GM147557
Informations de copyright
© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.
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