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Bioorg Med Chem Lett. 2016 Jul 1;26(13):3127-3134. doi: 10.1016/j.bmcl.2016.04.089. Epub 2016 May 4.

GroEL/ES inhibitors as potential antibiotics.

Author information

1
Indiana University, School of Medicine, Department of Biochemistry and Molecular Biology, 635 Barnhill Dr., Indianapolis, IN 46202, United States.
2
The University of Arizona, College of Pharmacy, Department of Pharmacology and Toxicology, 1703 E. Mabel St., PO Box 210207, Tucson, AZ 85721, United States.
3
Indiana University-Purdue University Indianapolis, Department of Biology, 723 W. Michigan St., Indianapolis, IN 46202, United States.
4
The Scripps Research Institute, Department of Chemistry, 10550 North Torrey Pines Rd., La Jolla, CA 92037, United States.
5
HHMI, Department of Genetics, Yale School of Medicine, Boyer Center for Molecular Medicine, 295 Congress Ave., New Haven, CT 06510, United States.
6
Indiana University, School of Medicine, Department of Biochemistry and Molecular Biology, 635 Barnhill Dr., Indianapolis, IN 46202, United States. Electronic address: johnstm@iu.edu.

Abstract

We 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.

KEYWORDS:

Antibiotics; Chaperonin; ESKAPE pathogens; GroEL; GroES; HSP10; HSP60; Molecular chaperone; Proteostasis; Small molecule inhibitors

PMID:
27184767
DOI:
10.1016/j.bmcl.2016.04.089
[Indexed for MEDLINE]
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