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-lM 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.
| Identifer | oai:union.ndltd.org:arizona.edu/oai:arizona.openrepository.com:10150/618724 |
| Date | 07 1900 |
| Creators | Abdeen, Sanofar, Salim, Nilshad, Mammadova, Najiba, Summers, Corey M., Frankson, Rochelle, Ambrose, Andrew J., Anderson, Gregory G., Schultz, Peter G., Horwich, Arthur L., Chapman, Eli, Johnson, Steven M. |
| Contributors | The University of Arizona, College of Pharmacy, Department of Pharmacology and Toxicology |
| Publisher | Elsevier |
| Source Sets | University of Arizona |
| Language | English |
| Detected Language | English |
| Type | Article |
| Rights | © 2016 Elsevier Ltd. All rights reserved. |
| Relation | http://linkinghub.elsevier.com/retrieve/pii/S0960894X16304772 |
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