TY - JOUR
T1 - Sulfonamido-2-arylbenzoxazole GroEL/ES Inhibitors as Potent Antibacterials against Methicillin-Resistant Staphylococcus aureus (MRSA)
AU - Abdeen, Sanofar
AU - Kunkle, Trent
AU - Salim, Nilshad
AU - Ray, Anne Marie
AU - Mammadova, Najiba
AU - Summers, Corey
AU - Stevens, McKayla
AU - Ambrose, Andrew J.
AU - Park, Yangshin
AU - Schultz, Peter G.
AU - Horwich, Arthur L.
AU - Hoang, Quyen Q.
AU - Chapman, Eli
AU - Johnson, Steven M.
N1 - Funding Information:
Research reported in this publication was supported by the National Institute of General Medical Sciences (NIGMS) of the National Institutes of Health (NIH) under Award Number R01GM120350. Q.Q.H. and Y.P. additionally acknowledge support from NIH Grants 5R01GM111639 and 5R01GM115844. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. This work was also supported, in part, by the Howard Hughes Medical Institute (AH), an IU Biomedical Research Grant (SMJ), and startup funds from the IU School of Medicine (SMJ) and the University of Arizona (EC). 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.
Publisher Copyright:
© 2018 American Chemical Society.
PY - 2018/8/23
Y1 - 2018/8/23
N2 - Extending from a study we recently published examining the antitrypanosomal effects of a series of GroEL/ES inhibitors based on a pseudosymmetrical bis-sulfonamido-2-phenylbenzoxazole scaffold, here, we report the antibiotic effects of asymmetric analogs of this scaffold against a panel of bacteria known as the ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species). While GroEL/ES inhibitors were largely ineffective against K. pneumoniae, A. baumannii, P. aeruginosa, and E. cloacae (Gram-negative bacteria), many analogs were potent inhibitors of E. faecium and S. aureus proliferation (Gram-positive bacteria, EC50 values of the most potent analogs were in the 1-2 μM range). Furthermore, even though some compounds inhibit human HSP60/10 biochemical functions in vitro (IC50 values in the 1-10 μM range), many of these exhibited moderate to low cytotoxicity to human liver and kidney cells (CC50 values > 20 μM).
AB - Extending from a study we recently published examining the antitrypanosomal effects of a series of GroEL/ES inhibitors based on a pseudosymmetrical bis-sulfonamido-2-phenylbenzoxazole scaffold, here, we report the antibiotic effects of asymmetric analogs of this scaffold against a panel of bacteria known as the ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species). While GroEL/ES inhibitors were largely ineffective against K. pneumoniae, A. baumannii, P. aeruginosa, and E. cloacae (Gram-negative bacteria), many analogs were potent inhibitors of E. faecium and S. aureus proliferation (Gram-positive bacteria, EC50 values of the most potent analogs were in the 1-2 μM range). Furthermore, even though some compounds inhibit human HSP60/10 biochemical functions in vitro (IC50 values in the 1-10 μM range), many of these exhibited moderate to low cytotoxicity to human liver and kidney cells (CC50 values > 20 μM).
UR - http://www.scopus.com/inward/record.url?scp=85051216559&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85051216559&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.8b00989
DO - 10.1021/acs.jmedchem.8b00989
M3 - Article
C2 - 30060666
AN - SCOPUS:85051216559
VL - 61
SP - 7345
EP - 7357
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 16
ER -