GroEL/ES inhibitors as potential antibiotics

Sanofar Abdeen, Nilshad Salim, Najiba Mammadova, Corey M. Summers, Rochelle Frankson, Andrew J. Ambrose, Gregory G. Anderson, Peter G. Schultz, Arthur L. Horwich, Eli Chapman, Steven M. Johnson

Research output: Contribution to journalArticle

15 Scopus citations

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-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.

Original languageEnglish (US)
Pages (from-to)3127-3134
Number of pages8
JournalBioorganic and Medicinal Chemistry Letters
Volume26
Issue number13
DOIs
StatePublished - Jul 1 2016

Keywords

  • Antibiotics
  • Chaperonin
  • ESKAPE pathogens
  • GroEL
  • GroES
  • HSP10
  • HSP60
  • Molecular chaperone
  • Proteostasis
  • Small molecule inhibitors

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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  • Cite this

    Abdeen, S., Salim, N., Mammadova, N., Summers, C. M., Frankson, R., Ambrose, A. J., Anderson, G. G., Schultz, P. G., Horwich, A. L., Chapman, E., & Johnson, S. M. (2016). GroEL/ES inhibitors as potential antibiotics. Bioorganic and Medicinal Chemistry Letters, 26(13), 3127-3134. https://doi.org/10.1016/j.bmcl.2016.04.089