Phenylthiazole Antibacterial Agents Targeting Cell Wall Synthesis Exhibit Potent Activity in Vitro and in Vivo against Vancomycin-Resistant Enterococci

J Med Chem. 2017 Mar 23;60(6):2425-2438. doi: 10.1021/acs.jmedchem.6b01780. Epub 2017 Mar 15.


The emergence of antibiotic-resistant bacterial species, such as vancomycin-resistant enterococci (VRE), necessitates the development of new antimicrobials. Here, we investigate the spectrum of antibacterial activity of three phenylthiazole-substituted aminoguanidines. These compounds possess potent activity against VRE, inhibiting growth of clinical isolates at concentrations as low as 0.5 μg/mL. The compounds exerted a rapid bactericidal effect, targeting cell wall synthesis. Transposon mutagenesis suggested three possible targets: YubA, YubB (undecaprenyl diphosphate phosphatase (UPPP)), and YubD. Both UPPP as well as undecaprenyl diphosphate synthase were inhibited by compound 1. YubA and YubD are annotated as transporters and may also be targets because 1 collapsed the proton motive force in membrane vesicles. Using Caenorhabditis elegans, we demonstrate that two compounds (1, 3, at 20 μg/mL) retain potent activity in vivo, significantly reducing the burden of VRE in infected worms. Taken altogether, the results indicate that compounds 1 and 3 warrant further investigation as novel antibacterial agents against drug-resistant enterococci.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Anti-Bacterial Agents / chemistry*
  • Anti-Bacterial Agents / pharmacology*
  • Caenorhabditis elegans
  • Cell Wall / drug effects
  • Gram-Positive Bacterial Infections / drug therapy*
  • Gram-Positive Bacterial Infections / microbiology
  • Humans
  • Microbial Sensitivity Tests
  • Models, Molecular
  • Thiazoles / chemistry*
  • Thiazoles / pharmacology*
  • Vancomycin Resistance
  • Vancomycin-Resistant Enterococci / drug effects*


  • Anti-Bacterial Agents
  • Thiazoles