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    GroEL/ES inhibitors as potential antibiotics

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    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. cc
    Show allShow less
    Affiliation
    The University of Arizona, College of Pharmacy, Department of Pharmacology and Toxicology
    Issue Date
    2016-07
    Keywords
    GroEL
    GroES
    HSP60
    HSP10
    Molecular chaperone
    Chaperonin
    Proteostasis
    Small molecule inhibitors
    ESKAPE pathogens
    Antibiotics
    
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    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
    Version
    Final Accepted Manuscript
    Additional Links
    http://linkinghub.elsevier.com/retrieve/pii/S0960894X16304772
    ae974a485f413a2113503eed53cd6c53
    10.1016/j.bmcl.2016.04.089
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