GroEL/ES inhibitors as potential antibiotics

• Published in: Bioorganic & medicinal chemistry letters Vol. 26; no. 13; pp. 3127 - 3134
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-07-2016
• Subjects: Acinetobacter baumannii; Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antibiotics; Bacillus subtilis; Cell Line; Chaperonin; Chaperonin 10 - antagonists & inhibitors; Chaperonin 10 - metabolism; Chaperonin 60 - antagonists & inhibitors; Chaperonin 60 - metabolism; Dose-Response Relationship, Drug; Enterobacter cloacae; Enterococcus faecium; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Escherichia coli; ESKAPE pathogens; Gram-Negative Bacteria - drug effects; Gram-Negative Bacteria - enzymology; Gram-Positive Bacteria - drug effects; GroEL; GroES; HSP10; HSP60; Humans; Klebsiella pneumoniae; Microbial Sensitivity Tests; Molecular chaperone; Molecular Structure; Proteostasis; Pseudomonas aeruginosa; Small molecule inhibitors; Staphylococcus aureus; Structure-Activity Relationship; Chaperonin; HSP60; Proteostasis; ESKAPE pathogens; Antibiotics; GroEL; HSP10; Small molecule inhibitors; GroES; Molecular chaperone
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2016.04.089

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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-μM 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.