Spore germination pathway in Clostridioides difficile and its pharmacological intervention

ABSTRACT Clostridioides difficile is an anaerobic Gram-positive bacterium that colonizes the gut of patients treated with broad-spectrum antibiotics. A challenge in treating C. difficile infection (CDI) is the production of spores that germinate to active vegetative cells in response to host bile acids. The normal gut microflora typically prevents

colonization of C. difficile. Gut microflora dysbiosis as a consequence of treatment with broad-spectrum antibiotics causes recurrence of CDI in 25% of patients, for which spore germination is an instigator. There are no antibiotics for the treatment of multiple recurrent CDI, leading to 11,500 annual deaths in the United States.

CDI is the deadliest of the five bacterial urgent threats. Understanding the process of spore germination is key to elucidating the basis for recurrent CDI. If spore germination could be prevented, the nefarious cycles of CDI can be interrupted. We disclose the discovery of the oxadiazoles with bactericidal activity against C. difficile

vegetative cells, of which certain oxadiazoles also inhibit spore germination. This grant proposal is outlined in three Specific Aims. We disclose our efforts in elucidation of the details of the spore-germination pathway (Specific Aim 1). We have proposed experiments to demonstrate that inhibition of spore germination is at the

root of recurrence of CDI (Specific Aim 2). Furthermore, we outline our efforts to intervene pharmacologically in recurrent CDI by inhibition of spore germination (Specific Aim 3).