A dual-action antibiotic that kills Clostridioides difficile vegetative cells and inhibits spore germination

Significance Clostridioides difficile infection (CDI) is the most lethal bacterial urgent public health threat, with recurrence of infection observed in 25% of patients. A challenge in treating CDI is the production of spores. CDI depends on spore germination for the initial infection and for recurrence. The current clinically used antibiotics do not inhibit spore germination. We report on the discovery of an antibiotic from the oxadiazole class that kills C. difficile vegetative cells and inhibits spore germination. The oxadiazole binds SleC, which degrades the spore cortex peptidoglycan in spore germination, and CspC, which senses germinants and cogerminants. Inhibition of the former takes place with high affinity.

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