Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 66, Issue 20, Pages 13891-13899Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.3c01249
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Clostridioides difficile infection (CDI) caused by dysbiosis after broad-spectrum antibiotic treatment is a major concern. In this study, an oxadiazole antibiotic compound, 3-(4-(cyclopentyloxy)phenyl)-5-(4-nitro-1H-imidazol-2-yl)-1,2,4-oxadiazole (compound 57), was found to exhibit potent and selective bactericidal activity against C. difficile.
Clostridioides difficile is an anaerobic Gram-positive bacterium that colonizes the gut of patients treated with broad-spectrum antibiotics. The normal gut microflora prevents C. difficile colonization; however, dysbiosis by treatment with broad-spectrum antibiotics causes recurrent C. difficile infection (CDI) in 25% of patients. There are no fully effective antibiotics for multiple recurrent CDIs. We report herein that oxadiazole antibiotics exhibit bactericidal activity against C. difficile vegetative cells. We screened a library of 75 oxadiazoles against C. difficile ATCC 43255. The findings from this collection served as the basis for the syntheses of an additional 58 analogs, which were tested against the same strain. We report a potent (MIC50 = 0.5 mu g/mL and MIC90 = 1 mu g/mL values for 101 C. difficile strains) and narrow-spectrum oxadiazole (3-(4-(cyclopentyloxy)phenyl)-5-(4-nitro-1H-imidazol-2-yl)-1,2,4-oxadiazole; compound 57), which is not active against common gut bacteria or other tested organisms. Compound 57 is selectively bactericidal against C. difficile and targets cell-wall synthesis.
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