Screening for potent and selective anticlostridial leads among FDA-approved drugs.

The Journal of Antibiotics
Ahmed AbdelKhalekMohamed N Seleem

Abstract

Clostridium difficile is a leading cause of morbidity and mortality particularly in hospital settings. In addition, treatment is very challenging due to the scarcity of effective therapeutic options. Thus, there remains an unmet need to identify new therapeutic agents capable of treating C. difficile infections. In the current study, we screened two FDA-approved drug libraries against C. difficile. Out of almost 3200 drugs screened, 50 drugs were capable of inhibiting the growth of C. difficile. Remarkably, some of the potent inhibitors have never been reported before and showed activity in a clinically achievable range. Structure-activity relationship analysis of the active hits clustered the potent inhibitors into four chemical groups; nitroimidazoles (MIC50 = 0.06-2.7 μM), salicylanilides (MIC50 = 0.2-0.6 μM), imidazole antifungals (MIC50 = 4.8-11.6 μM), and miscellaneous group (MIC50 = 0.4-22.2 μM). The most potent drugs from the initial screening were further evaluated against additional clinically relevant strains of C. difficile. Moreover, we tested the activity of potent inhibitors against representative strains of human normal gut microbiota to investigate the selectivity of the inhibitors towards C. difficile. Overall...Continue Reading

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Citations

Oct 13, 2020·International Journal of Antimicrobial Agents·Ahmed AbdelKhalek, Mohamed N Seleem
Mar 31, 2021·Scientific Reports·Nader S Abutaleb, Mohamed N Seleem
Sep 23, 2020·Journal of Medicinal Chemistry·George A NaclerioHerman O Sintim

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