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dc.contributor.authorAbdeen, Sanofar
dc.contributor.authorSalim, Nilshad
dc.contributor.authorMammadova, Najiba
dc.contributor.authorSummers, Corey M.
dc.contributor.authorFrankson, Rochelle
dc.contributor.authorAmbrose, Andrew J.
dc.contributor.authorAnderson, Gregory G.
dc.contributor.authorSchultz, Peter G.
dc.contributor.authorHorwich, Arthur L.
dc.contributor.authorChapman, Eli
dc.contributor.authorJohnson, Steven M.
dc.date.accessioned2016-08-24T01:27:14Z
dc.date.available2016-08-24T01:27:14Z
dc.date.issued2016-07
dc.identifier.citationGroEL/ES inhibitors as potential antibiotics 2016, 26 (13):3127 Bioorganic & Medicinal Chemistry Lettersen
dc.identifier.issn0960894X
dc.identifier.pmid27184767
dc.identifier.doi10.1016/j.bmcl.2016.04.089
dc.identifier.urihttp://hdl.handle.net/10150/618724
dc.description.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.
dc.language.isoenen
dc.publisherElsevieren
dc.relation.urlhttp://linkinghub.elsevier.com/retrieve/pii/S0960894X16304772en
dc.rights© 2016 Elsevier Ltd. All rights reserved.en
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/
dc.subjectGroEL
dc.subjectGroES
dc.subjectHSP60
dc.subjectHSP10
dc.subjectMolecular chaperone
dc.subjectChaperonin
dc.subjectProteostasis
dc.subjectSmall molecule inhibitors
dc.subjectESKAPE pathogens
dc.subjectAntibiotics
dc.titleGroEL/ES inhibitors as potential antibioticsen
dc.typeArticleen
dc.contributor.departmentThe University of Arizona, College of Pharmacy, Department of Pharmacology and Toxicology
dc.identifier.journalBioorganic & Medicinal Chemistry Lettersen
dc.description.noteAvailable online 4 May 2016; 24 month embargo
dc.description.collectioninformationThis 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.en
dc.eprint.versionFinal Accepted Manuscript
refterms.dateFOA2018-05-04T00:00:00Z
html.description.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.


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