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

The Journal of Antibiotics volume 73, pages 392–409 (2020)Cite this article

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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, this study provides a platform that could be used for further development of potent and selective anticlostridial antibiotics.

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Acknowledgements

This work was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under Award Number R01AI130186.

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Authors and Affiliations

  1. Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, IN, 47907, USA

    Ahmed AbdelKhalek, Haroon Mohammad & Mohamed N. Seleem

  2. Department of Pharmaceutical Organic Chemistry, College of Pharmacy, Al-Azhar University, Cairo, 11884, Egypt

    Abdelrahman S. Mayhoub

  3. University of Science and Technology, Zewail City of Science and Technology, Giza, 12578, Egypt

    Abdelrahman S. Mayhoub

  4. Purdue Institute of Inflammation, Immunology, and Infectious Disease, West Lafayette, IN, 47907, USA

    Mohamed N. Seleem

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  1. Ahmed AbdelKhalek
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Correspondence to Mohamed N. Seleem.

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AbdelKhalek, A., Mohammad, H., Mayhoub, A.S. et al. Screening for potent and selective anticlostridial leads among FDA-approved drugs. J Antibiot 73, 392–409 (2020). https://doi.org/10.1038/s41429-020-0288-3

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