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

Haroon Mohammad, Waleed Younis, Lu Chen, Christine E. Peters, Joe Pogliano, Kit Pogliano, Bruce Cooper, Jianan Zhang, Abdelrahman Mayhoub, Eric Oldfield, Mark Cushman, Mohamed N. Seleem

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)2425-2438
Number of pages14
JournalJournal of Medicinal Chemistry
Volume60
Issue number6
DOIs
StatePublished - Mar 23 2017

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ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Mohammad, H., Younis, W., Chen, L., Peters, C. E., Pogliano, J., Pogliano, K., Cooper, B., Zhang, J., Mayhoub, A., Oldfield, E., Cushman, M., & Seleem, M. N. (2017). Phenylthiazole Antibacterial Agents Targeting Cell Wall Synthesis Exhibit Potent Activity in Vitro and in Vivo against Vancomycin-Resistant Enterococci. Journal of Medicinal Chemistry, 60(6), 2425-2438. https://doi.org/10.1021/acs.jmedchem.6b01780