Persistent Link:
http://hdl.handle.net/10150/618724
Title:
GroEL/ES inhibitors as potential antibiotics
Author:
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. ( 0000-0001-7254-4128 )
Affiliation:
The University of Arizona, College of Pharmacy, Department of Pharmacology and Toxicology
Issue Date:
2016-07
Publisher:
Elsevier
Citation:
GroEL/ES inhibitors as potential antibiotics 2016, 26 (13):3127 Bioorganic & Medicinal Chemistry Letters
Journal:
Bioorganic & Medicinal Chemistry Letters
Rights:
© 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 embargo
ISSN:
0960894X
PubMed ID:
27184767
DOI:
10.1016/j.bmcl.2016.04.089
Keywords:
GroEL; GroES; HSP60; HSP10; Molecular chaperone; Chaperonin; Proteostasis; Small molecule inhibitors; ESKAPE pathogens; Antibiotics
Version:
Final Accepted Manuscript
Additional Links:
http://linkinghub.elsevier.com/retrieve/pii/S0960894X16304772

Full metadata record

DC FieldValue Language
dc.contributor.authorAbdeen, Sanofaren
dc.contributor.authorSalim, Nilshaden
dc.contributor.authorMammadova, Najibaen
dc.contributor.authorSummers, Corey M.en
dc.contributor.authorFrankson, Rochelleen
dc.contributor.authorAmbrose, Andrew J.en
dc.contributor.authorAnderson, Gregory G.en
dc.contributor.authorSchultz, Peter G.en
dc.contributor.authorHorwich, Arthur L.en
dc.contributor.authorChapman, Elien
dc.contributor.authorJohnson, Steven M.en
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.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-

Related articles on PubMed

All Items in UA Campus Repository are protected by copyright, with all rights reserved, unless otherwise indicated.