2. Academic Validation
  3. Hydroxybiphenylamide GroEL/ES Inhibitors Are Potent Antibacterials against Planktonic and Biofilm Forms of Staphylococcus aureus

Hydroxybiphenylamide GroEL/ES Inhibitors Are Potent Antibacterials against Planktonic and Biofilm Forms of Staphylococcus aureus

  • J Med Chem. 2018 Dec 13;61(23):10651-10664. doi: 10.1021/acs.jmedchem.8b01293.
Trent Kunkle 1,  Sanofar Abdeen 1,  Nilshad Salim 1,  Anne-Marie Ray 1,  Mckayla Stevens 1,  Andrew J Ambrose 2,  José Victorino 1,  Yangshin Park 1 3 4,  Quyen Q Hoang 1 3 4,  Eli Chapman 2,  Steven M Johnson 1
Affiliations

Affiliations

  • 1 Department of Biochemistry and Molecular Biology , Indiana University School of Medicine , 635 Barnhill Drive , Indianapolis , Indiana 46202 , United States.
  • 2 Department of Pharmacology and Toxicology, College of Pharmacy , The University of Arizona , 1703 E. Mabel Street , P.O. Box 210207, Tucson , Arizona 85721 , United States.
  • 3 Stark Neurosciences Research Institute , Indiana University School of Medicine , 320 W. 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.
PMID: 30392371 DOI: 10.1021/acs.jmedchem.8b01293
Abstract

We recently reported the identification of a GroEL/ES inhibitor (1, N-(4-(benzo[ d]thiazol-2-ylthio)-3-chlorophenyl)-3,5-dibromo-2-hydroxybenzamide) that exhibited in vitro Antibacterial effects against Staphylococcus aureus comparable to vancomycin, an Antibiotic of last resort. To follow up, we have synthesized 43 compound 1 analogs to determine the most effective functional groups of the scaffold for inhibiting GroEL/ES and killing bacteria. Our results identified that the benzothiazole and hydroxyl groups are important for inhibiting GroEL/ES-mediated folding functions, with the hydroxyl essential for Antibacterial effects. Several analogs exhibited >50-fold selectivity indices between Antibacterial efficacy and cytotoxicity to human liver and kidney cells in Cell Culture. We found that MRSA was not able to easily generate acute resistance to lead inhibitors in a gain-of-resistance assay and that lead inhibitors were able to permeate through established S. aureus biofilms and maintain their bactericidal effects.

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