Abdeen, SanofarSalim, NilshadMammadova, NajibaSummers, CoreyFrankson, RochelleAmbrose, Andrew J.Anderson, Gregory G.Schultz, Peter G.Horwich, Arthur L.Chapman, EliJohnson, Steven M.2017-01-252017-01-252016-07Abdeen, S., Salim, N., Mammadova, N., Summers, C. M., Frankson, R., Ambrose, A. J., … Johnson, S. M. (2016). GroEL/ES inhibitors as potential antibiotics. Bioorganic & Medicinal Chemistry Letters, 26(13), 3127–3134. https://doi.org/10.1016/j.bmcl.2016.04.089https://hdl.handle.net/1805/11852We recently reported results from a high-throughput screening effort that identified 235 inhibitors of the Escherichia coli GroEL/ES chaperonin system [Bioorg. Med. Chem. Lett.2014, 24, 786]. As the GroEL/ES chaperonin system is essential for growth under all conditions, we reasoned that targeting GroEL/ES with small molecule inhibitors could be a viable antibacterial strategy. Extending from our initial screen, we report here the antibacterial activities of 22 GroEL/ES inhibitors against a panel of Gram-positive and Gram-negative bacteria, including E. coli, Bacillus subtilis, Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter cloacae. GroEL/ES inhibitors were more effective at blocking the proliferation of Gram-positive bacteria, in particular S. aureus, where lead compounds exhibited antibiotic effects from the low-μM to mid-nM range. While several compounds inhibited the human HSP60/10 refolding cycle, some were able to selectively target the bacterial GroEL/ES system. Despite inhibiting HSP60/10, many compounds exhibited low to no cytotoxicity against human liver and kidney cell lines. Two lead candidates emerged from the panel, compounds 8 and 18, that exhibit >50-fold selectivity for inhibiting S. aureus growth compared to liver or kidney cell cytotoxicity. Compounds 8 and 18 inhibited drug-sensitive and methicillin-resistant S. aureus strains with potencies comparable to vancomycin, daptomycin, and streptomycin, and are promising candidates to explore for validating the GroEL/ES chaperonin system as a viable antibiotic target.enPublisher PolicyGroELGroESmolecular chaperoneproteostasisArticle