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. Epub 2018 Nov 15.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amides / chemistry*
  • Amides / pharmacology*
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology
  • Biofilms / drug effects*
  • Biofilms / growth & development
  • Chaperonin 10 / antagonists & inhibitors*
  • Chaperonin 60 / antagonists & inhibitors*
  • HEK293 Cells
  • Humans
  • Staphylococcus aureus / drug effects*
  • Staphylococcus aureus / growth & development
  • Staphylococcus aureus / physiology*


  • Amides
  • Anti-Bacterial Agents
  • Chaperonin 10
  • Chaperonin 60