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

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

Author information

1
Department of Comparative Pathobiology, Purdue University College of Veterinary Medicine , West Lafayette, Indiana 47907, United States.
2
Department of Biochemistry, University of Illinois at Urbana-Champaign , Urbana, Illinois 61801, United States.
3
Division of Biological Sciences, University of California, San Diego , La Jolla, California 92093, United States.
4
Bindley Bioscience Center, Purdue University , West Lafayette, Indiana 47907, United States.
5
School of Molecular and Cellular Biology, University of Illinois at Urbana-Champaign , Urbana, Illinois 61801, United States.
6
Department of Pharmaceutical Organic Chemistry, College of Pharmacy, Al-Azhar University , Cairo, 11884, Egypt.
7
Biomedical Sciences, University of Science and Technology, Zewail City of Science and Technology , Giza, Egypt.
8
Center for Biophysics and Quantitative Biology, University of Illinois at Urbana-Champaign , Urbana, Illinois 61801, United States.
9
Department of Chemistry, University of Illinois at Urbana-Champaign , Urbana, Illinois 61801, United States.
10
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University College of Pharmacy and the Purdue Center for Cancer Research , West Lafayette, Indiana 47907, United States.
11
Purdue Institute for Inflammation, Immunology, and Infectious Disease, Purdue University , West Lafayette, Indiana 47907, United States.

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.

PMID:
28248504
PMCID:
PMC5437844
DOI:
10.1021/acs.jmedchem.6b01780
[Indexed for MEDLINE]
Free PMC Article

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