Summers, Corey M.
Ambrose, Andrew J.
Anderson, Gregory G.
Schultz, Peter G.
Horwich, Arthur L.
Johnson, Steven M.
AffiliationThe University of Arizona, College of Pharmacy, Department of Pharmacology and Toxicology
Small molecule inhibitors
MetadataShow full item record
CitationGroEL/ES inhibitors as potential antibiotics 2016, 26 (13):3127 Bioorganic & Medicinal Chemistry Letters
Rights© 2016 Elsevier Ltd. All rights reserved.
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AbstractWe 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.
NoteAvailable online 4 May 2016; 24 month embargo
VersionFinal Accepted Manuscript
- Sulfonamido-2-arylbenzoxazole GroEL/ES Inhibitors as Potent Antibacterials against Methicillin-Resistant Staphylococcus aureus (MRSA).
- Authors: Abdeen S, Kunkle T, Salim N, Ray AM, Mammadova N, Summers C, Stevens M, Ambrose AJ, Park Y, Schultz PG, Horwich AL, Hoang QQ, Chapman E, Johnson SM
- Issue date: 2018 Aug 23
- HSP60/10 chaperonin systems are inhibited by a variety of approved drugs, natural products, and known bioactive molecules.
- Authors: Stevens M, Abdeen S, Salim N, Ray AM, Washburn A, Chitre S, Sivinski J, Park Y, Hoang QQ, Chapman E, Johnson SM
- Issue date: 2019 May 1
- Functional Differences between E. coli and ESKAPE Pathogen GroES/GroEL.
- Authors: Sivinski J, Ambrose AJ, Panfilenko I, Zerio CJ, Machulis JM, Mollasalehi N, Kaneko LK, Stevens M, Ray AM, Park Y, Wu C, Hoang QQ, Johnson SM, Chapman E
- Issue date: 2021 Jan 12
- Hydroxybiphenylamide GroEL/ES Inhibitors Are Potent Antibacterials against Planktonic and Biofilm Forms of Staphylococcus aureus.
- Authors: Kunkle T, Abdeen S, Salim N, Ray AM, Stevens M, Ambrose AJ, Victorino J, Park Y, Hoang QQ, Chapman E, Johnson SM
- Issue date: 2018 Dec 13
- Analogs of nitrofuran antibiotics are potent GroEL/ES inhibitor pro-drugs.
- Authors: Stevens M, Howe C, Ray AM, Washburn A, Chitre S, Sivinski J, Park Y, Hoang QQ, Chapman E, Johnson SM
- Issue date: 2020 Aug 30