Author
Abdeen, SanofarSalim, 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.

Affiliation
The University of Arizona, College of Pharmacy, Department of Pharmacology and ToxicologyIssue Date
2016-07Keywords
GroELGroES
HSP60
HSP10
Molecular chaperone
Chaperonin
Proteostasis
Small molecule inhibitors
ESKAPE pathogens
Antibiotics
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Show full item recordPublisher
ElsevierCitation
GroEL/ES inhibitors as potential antibiotics 2016, 26 (13):3127 Bioorganic & Medicinal Chemistry LettersRights
© 2016 Elsevier Ltd. All rights reserved.Collection Information
This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.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-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.Note
Available online 4 May 2016; 24 month embargoISSN
0960894XPubMed ID
27184767Version
Final Accepted ManuscriptAdditional Links
http://linkinghub.elsevier.com/retrieve/pii/S0960894X16304772ae974a485f413a2113503eed53cd6c53
10.1016/j.bmcl.2016.04.089
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