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Benzimidazole-Based FabI Inhibitors: A Promising Novel Scaffold for Anti-staphylococcal Drug Development

journal contribution
posted on 06.05.2022, 15:51 by Tina L Mistry, Lena Truong, Arun K Ghosh, Michael JohnsonMichael Johnson, Shahila Mehboob
The enoyl-ACP reductase (FabI) enzyme is a well validated target for anti-staphylococcal drug discovery and development. With the goal of finding alternate therapeutics for drug-resistant strains of Staphylococcus aureus, such as methicillin-resistant S. aureus (MRSA), our previously published series of benzimidazole-based inhibitors of the FabI enzyme from Francisella tularensis (FtFabI) have been evaluated against FabI from S. aureus (SaFabI). We report here the preliminary structure-activity relationship of this series and the prioritization of compounds toward lead optimization. Mutational studies have identified key residues that contribute toward stabilizing the inhibitors in the active site of FabI. Mutations that do not significantly impact enzyme function but destabilize inhibitor binding are more likely to occur in nature as organisms evolve to evade the action of antibiotics leading to resistance. Identifying these residues provides guidance for minimizing susceptibility to resistance. Additionally, we have identified compounds that elicit antibacterial activity through off-target effects and observe that close analogs can display differing modes of action (on-target vs off-target) and need to be individually evaluated early on to prioritize compounds for lead optimization. Overall, our data suggest that the benzimidazole scaffold is a promising scaffold for anti-staphylococcal drug development.

Funding

Novel Antibiotic Development For Biodefense | Funder: National Institutes of Health (National Institute of Allergy and Infectious Diseases) | Grant ID: U01AI077949

Development of novel dual-mode antibiotics for drug resistant S. aureus | Funder: National Institute of Allergy and Infectious Diseases | Grant ID: R41AI110090

History

Citation

Mistry, T. L., Truong, L., Ghosh, A. K., Johnson, M. E.Mehboob, S. (2016). Benzimidazole-Based FabI Inhibitors: A Promising Novel Scaffold for Anti-staphylococcal Drug Development. ACS Infectious Diseases, 3(1), 54-61. https://doi.org/10.1021/acsinfecdis.6b00123

Publisher

American Chemical Society (ACS)

Language

en

issn

2373-8227