Small-molecule suppression of β-lactam resistance in multidrug-resistant gram-negative pathogens

J Med Chem. 2014 Sep 11;57(17):7450-8. doi: 10.1021/jm501050e. Epub 2014 Aug 28.

Abstract

Recent efforts toward combating antibiotic resistance in bacteria have focused on Gram-positive bacteria; however, multidrug-resistant Gram-negative bacteria pose a significant risk to public health. An orthogonal approach to the development of new antibiotics is to develop adjuvant compounds that enhance the susceptibility of drug-resistant strains of bacteria to currently approved antibiotics. This paper describes the synthesis and biological activity of a library of aryl amide 2-aminoimidazoles based on a lead structure from an initial screen. A small molecule was identified from this library that is capable of lowering the minimum inhibitory concentration of β-lactam antibiotics by up to 64-fold.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cell Line
  • Cell Survival / drug effects
  • Drug Resistance, Multiple, Bacterial / drug effects*
  • Gram-Negative Bacteria / classification
  • Gram-Negative Bacteria / drug effects*
  • Hemolysis / drug effects
  • Humans
  • Keratinocytes / cytology
  • Keratinocytes / drug effects
  • Microbial Sensitivity Tests
  • Sheep
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*
  • beta-Lactam Resistance / drug effects*

Substances

  • Small Molecule Libraries