Targeting Narrow-spectrum Antibacterials and Spore Germination Inhibition to Halt Recurrence of Cloistridioides difficile Infection
Clostridioides difficile is an anaerobic spore-forming Gram-positive bacterium that is an urgent antibiotic resistant threat. The normal gut flora is resistant to C. difficile colonization. Broad-spectrum antibiotics disrupt the gut microflora, allowing for C. difficile colonization. The spores germinate in the presence of host bile acids to vegetative cells that produce toxins that damage the gut epithelia, promoting inflammation and diarrhea. The vegetative cells produce more spores, which are shed in feces or germinate to vegetative cells, resulting in recurrence of C. difficile infection in 25% of patients. We recently reported the discovery of a 1,2,4-oxadiazole (compound 1) as a new antibacterial agent with activity against C. difficle and efficacy in a mouse C. difficile infection model.1 This compound acts as a dual-action antibiotic, killing C. difficile vegetative cells and inhibiting spore germination. Furthermore, we screened a library of 133 additional oxadiazoles from our lab against C. difficile ATCC 43255. We discovered an oxadiazole (compound 2) with potent and selective bactericidal activity against vegetative C. difficile, sparing other Gram-positive, Gram-negative, and major gut bacteria.2 We also evaluated 125 oxadiazoles for spore germination inhibition. We discovered oxadiazole 3 with poor activity against vegetative C. difficile and four-fold more potent inhibition of spore germination as compound 1. The oxadiazoles target penicillin-binding proteins (PBPs) for inhibition, which leads to a damaged cell cell. The mechanism of action of the oxadiazoles in is inhibition of SleC, a lytic transglycosylate that turns over the spore peptidoglycan in triggering spore germination.
References
[1] Janardhanan, J. et al. A dual-action antibiotic that kills Clostridioides difficile vegetative cells and inhibits spore germination. Proc. Nat. Acad. Sci. 2023, 120, e2304110120.
[2] Qian, Y. et al. A potent and narrow-spectrum antibacterial against Clostridioides difficile infection. J. Med. Chem. 2023, 66, 13891–13899.
