GroEL/ES inhibitors as potential antibiotics

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:26

Article

Abdeen, Sanofar¹  Salim, Nilshad¹  Mammadova, Najiba^1,6  Summers, Corey M.^1,7  Frankson, Rochelle^1,8  Ambrose, Andrew J.²  Anderson, Gregory G.³  Schultz, Peter G.⁴  Horwich, Arthur L.⁵  Chapman, Eli²  Johnson, Steven M.¹ 

[1] Indiana Univ Sch Med, Dept Biochem & Mol Biol, 635 Barnhill Dr, Indianapolis, IN 46202 USA

[2] Univ Arizona, Coll Pharm, Dept Pharmacol & Toxicol, 1703 E Mabel St,POB 210207, Tucson, AZ 85721 USA

[3] Indiana Univ Purdue Univ, Dept Biol, 723 W Michigan St, Indianapolis, IN 46202 USA

[4] Scripps Res Inst, Dept Chem, 10550 North Torrey Pines Rd, La Jolla, CA 92037 USA

[5] Yale Univ, Sch Med, Boyer Ctr Mol Med, HHMI,Dept Genet, 295 Congress Ave, New Haven, CT 06510 USA

[6] Iowa State Univ, Dept Genet Dev & Cell Biol, 1210 Mol Biol Bldg,Pannel Dr, Ames, IA 50011 USA

[7] Iowa State Univ, Dept Kinesiol, 235 Barbara E Forker Bldg,Beach Rd, Ames, IA 50011 USA

[8] Purdue Univ, Dept Med Chem & Mol Pharmacol, Hansen Life Sci Res Bldg,201 S Univ St, W Lafayette, IN 47907 USA

关键词: GroEL;    GroES;    HSP60;    HSP10;    Molecular chaperone;    Chaperonin;    Proteostasis;    Small molecule inhibitors;    ESKAPE pathogens;    Antibiotics;   

DOI  :  10.1016/j.bmcl.2016.04.089

来源: Elsevier

【 摘 要 】

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-mu M 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. (C) 2016 Elsevier Ltd. All rights reserved.

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