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J Med Chem. 2018 Aug 23;61(16):7345-7357. doi: 10.1021/acs.jmedchem.8b00989. Epub 2018 Aug 14.

Sulfonamido-2-arylbenzoxazole GroEL/ES Inhibitors as Potent Antibacterials against Methicillin-Resistant Staphylococcus aureus (MRSA).

Author information

1
Department of Biochemistry and Molecular Biology , Indiana University School of Medicine , 635 Barnhill Drive , Indianapolis , Indiana 46202 , United States.
2
College of Pharmacy, Department of Pharmacology and Toxicology , The University of Arizona , 1703 East Mabel Street , P.O. Box 210207, Tucson , Arizona 85721 , United States.
3
Stark Neurosciences Research Institute , Indiana University School of Medicine , 320 West 15th Street, Suite 414 , Indianapolis , Indiana 46202 , United States.
4
Department of Neurology , Indiana University School of Medicine , 635 Barnhill Drive , Indianapolis , Indiana 46202 , United States.
5
Department of Chemistry , The Scripps Research Institute , 10550 North Torrey Pines Road , La Jolla , California 92037 , United States.
6
HHMI, Department of Genetics, Yale School of Medicine , Boyer Center for Molecular Medicine , 295 Congress Avenue , New Haven , Connecticut 06510 , United States.

Abstract

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).

PMID:
30060666
PMCID:
PMC6345161
[Available on 2019-08-23]
DOI:
10.1021/acs.jmedchem.8b00989

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