A Potent and Narrow-Spectrum Antibacterial against Clostridioides difficile Infection.
Yuanyuan QianBiruk Tesfaye BirhanuJingdong YangDerong DingJeshina JanardhananShahriar MobasheryMayland ChangPublished in: Journal of medicinal chemistry (2023)
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 (MIC 50 = 0.5 μg/mL and MIC 90 = 1 μg/mL values for 101 C . difficile strains) and narrow-spectrum oxadiazole (3-(4-(cyclopentyloxy)phenyl)-5-(4-nitro-1 H -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.
Keyphrases
- clostridium difficile
- ejection fraction
- newly diagnosed
- escherichia coli
- induced apoptosis
- gram negative
- end stage renal disease
- microbial community
- oxidative stress
- anti inflammatory
- wastewater treatment
- mouse model
- cell death
- risk assessment
- endoplasmic reticulum stress
- smoking cessation
- anaerobic digestion
- replacement therapy
- silver nanoparticles