Products Cited in Publications Worldwide Potent and specific antibiotic combination therapy against Clostridioides difficile

Potent and specific antibiotic combination therapy against Clostridioides difficile

Vasiliki T. Chioti; Kirklin L. McWhorter; Tamra C. Blue; Yuchen Li; Fei Xu; Philip D. Jeffrey; Katherine M. Davis; Mohammad R. Seyedsayamdost

DOI: PMID:

Abstract

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 moiety and exhibit specifc antibiosis against Clostridioides difcile. Here we report the mechanism of action of keratinicyclin B (KCB). We fnd that steric constraints preclude KCB from binding peptidoglycan termini. Instead, KCB inhibits C. difcile 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. difcile 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 (VAN) shows highly synergistic and specifc antimicrobial activity, and that nanomolar combinations of the two drugs are sufcient for complete growth inhibition of C. difcile, while leaving common commensal strains unafected.

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