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 Johnson

Research output: Contribution to journalArticle

12 Citations (Scopus)

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

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Chaperonins
Cytotoxicity
Anti-Bacterial Agents
Liver
Escherichia coli
Staphylococcus aureus
Bacteria
Staphylococcal Pneumonia
Daptomycin
Lead compounds
Kidney
Enterobacter cloacae
Acinetobacter baumannii
Enterococcus faecium
Methicillin
Klebsiella pneumoniae
Gram-Positive Bacteria
Streptomycin
Bacilli
Vancomycin

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

Cite this

Abdeen, S., Salim, N., Mammadova, N., Summers, C. M., Frankson, R., Ambrose, A. J., ... Johnson, S. (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

GroEL/ES inhibitors as potential antibiotics. / 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.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 26, No. 13, 01.07.2016, p. 3127-3134.

Research output: Contribution to journalArticle

Abdeen, S, Salim, N, Mammadova, N, Summers, CM, Frankson, R, Ambrose, AJ, Anderson, GG, Schultz, PG, Horwich, AL, Chapman, E & Johnson, S 2016, 'GroEL/ES inhibitors as potential antibiotics', Bioorganic and Medicinal Chemistry Letters, vol. 26, no. 13, pp. 3127-3134. https://doi.org/10.1016/j.bmcl.2016.04.089
Abdeen S, Salim N, Mammadova N, Summers CM, Frankson R, Ambrose AJ et al. GroEL/ES inhibitors as potential antibiotics. Bioorganic and Medicinal Chemistry Letters. 2016 Jul 1;26(13):3127-3134. https://doi.org/10.1016/j.bmcl.2016.04.089
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. / GroEL/ES inhibitors as potential antibiotics. In: Bioorganic and Medicinal Chemistry Letters. 2016 ; Vol. 26, No. 13. pp. 3127-3134.
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AU - Anderson, Gregory G.

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