TY - JOUR
T1 - GroEL/ES inhibitors as potential antibiotics
AU - Abdeen, Sanofar
AU - Salim, Nilshad
AU - Mammadova, Najiba
AU - Summers, Corey M.
AU - Frankson, Rochelle
AU - Ambrose, Andrew J.
AU - Anderson, Gregory G.
AU - Schultz, Peter G.
AU - Horwich, Arthur L.
AU - Chapman, Eli
AU - Johnson, Steven M.
N1 - Funding Information:
We are grateful to the Genomics Institute of the Novartis Research Foundation for working with us on the previous high-throughput screening that initially identified these GroEL/ES biochemical inhibitors. We also thank Dr. Leendert Hamoen from the University of Amsterdam, Swammerdam Institute for Life Sciences (SILS) for the B. subtilis 168 cells. The human HSP60 expression plasmid (lacking the 26 amino acid N-terminal mitochondrial signal peptide) was generously donated by Dr. Abdussalam Azem from Tel Aviv University, Faculty of Life Sciences, Department of Biochemistry, Israel. We thank Dr. Quyen Hoang from the IU School of Medicine, Department of Biochemistry and Molecular Biology for helpful discussions and the use of various lab equipment. This work was supported in part by an IU Biomedical Research Grant , an IU Collaborative Research Grant , the Showalter Trust Foundation , and startup funds from the IU School of Medicine (S.M.J.) and the University of Arizona (E.C.).
Publisher Copyright:
© 2016 Elsevier Ltd. All rights reserved.
PY - 2016/7/1
Y1 - 2016/7/1
N2 - 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.
AB - 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.
KW - Antibiotics
KW - Chaperonin
KW - ESKAPE pathogens
KW - GroEL
KW - GroES
KW - HSP10
KW - HSP60
KW - Molecular chaperone
KW - Proteostasis
KW - Small molecule inhibitors
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U2 - 10.1016/j.bmcl.2016.04.089
DO - 10.1016/j.bmcl.2016.04.089
M3 - Article
C2 - 27184767
AN - SCOPUS:84966709489
VL - 26
SP - 3127
EP - 3134
JO - Bioorganic and Medicinal Chemistry Letters
JF - Bioorganic and Medicinal Chemistry Letters
SN - 0960-894X
IS - 13
ER -