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A novel series of enoyl reductase inhibitors targeting the ESKAPE pathogens, Staphylococcus aureus and Acinetobacter baumannii.

journal contribution
posted on 06.05.2022, 16:30 by Jieun Kwon, Tina Mistry, Jinhong Ren, Michael JohnsonMichael Johnson, Shahila Mehboob
S. aureus and A. baumannii are among the ESKAPE pathogens that are increasingly difficult to treat due to the rise in the number of drug resistant strains. Novel therapeutics targeting these pathogens are much needed. The bacterial enoyl reductase (FabI) is as potentially significant drug target for developing pathogen-specific antibiotics due to the presence of alternate FabI isoforms in many other bacterial species. We report the identification and development of a novel N-carboxy pyrrolidine scaffold targeting FabI in S. aureus and A. baumannii, two pathogens for which FabI essentiality has been established. This scaffold is unrelated to other known antibiotic families, and FabI is not targeted by any currently approved antibiotic. Our data shows that this scaffold displays promising enzyme inhibitory activity against FabI from both S. aureus and A. baumannii, as well as encouraging antibacterial activity in S. aureus. Compounds also display excellent synergy when combined with colistin and tested against A. baumannii. In this combination the MIC of colistin is reduced by 10-fold. Our first generation compound displays promising enzyme inhibition, targets FabI in S. aureus with a favorable selectivity index (ratio of cytotoxicity to MIC), and has excellent synergy with colistin against A. baumannii, including a multidrug resistant strain.

Funding

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

History

Citation

Kwon, J., Mistry, T., Ren, J., Johnson, M. E.Mehboob, S. (2017). A novel series of enoyl reductase inhibitors targeting the ESKAPE pathogens, Staphylococcus aureus and Acinetobacter baumannii. Bioorganic & Medicinal Chemistry, 26(1), 65-76. https://doi.org/10.1016/j.bmc.2017.11.018

Publisher

Elsevier BV

Language

en

issn

0968-0896