title: Phenylthiazole Antibacterial Agents Targeting Cell Wall Synthesis Exhibit Potent Activity in Vitro and in Vivo against Vancomycin-Resistant Enterococci.
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.
authors.affiliation: Department of Comparative Pathobiology, Purdue University College of Veterinary Medicine , West Lafayette, Indiana 47907, United States.
authors.forename: Haroon
authors.identifier: 0000-0002-8843-8933
authors.initials: H
authors.lastname: Mohammad
authors.affiliation: Department of Comparative Pathobiology, Purdue University College of Veterinary Medicine , West Lafayette, Indiana 47907, United States.
authors.forename: Waleed
authors.initials: W
authors.lastname: Younis
authors.affiliation: Department of Biochemistry, University of Illinois at Urbana-Champaign , Urbana, Illinois 61801, United States.
authors.forename: Lu
authors.initials: L
authors.lastname: Chen
authors.affiliation: Division of Biological Sciences, University of California, San Diego , La Jolla, California 92093, United States.
authors.forename: Christine E
authors.initials: CE
authors.lastname: Peters
authors.affiliation: Division of Biological Sciences, University of California, San Diego , La Jolla, California 92093, United States.
authors.forename: Joe
authors.initials: J
authors.lastname: Pogliano
authors.affiliation: Division of Biological Sciences, University of California, San Diego , La Jolla, California 92093, United States.
authors.forename: Kit
authors.initials: K
authors.lastname: Pogliano
authors.affiliation: Bindley Bioscience Center, Purdue University , West Lafayette, Indiana 47907, United States.
authors.forename: Bruce
authors.initials: B
authors.lastname: Cooper
authors.affiliation: School of Molecular and Cellular Biology, University of Illinois at Urbana-Champaign , Urbana, Illinois 61801, United States.
authors.forename: Jianan
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Pharmaceutical Organic Chemistry, College of Pharmacy, Al-Azhar University , Cairo, 11884, Egypt.|Biomedical Sciences, University of Science and Technology, Zewail City of Science and Technology , Giza, Egypt.
authors.forename: Abdelrahman
authors.identifier: 0000-0002-3987-3680
authors.initials: A
authors.lastname: Mayhoub
authors.affiliation: Center for Biophysics and Quantitative Biology, University of Illinois at Urbana-Champaign , Urbana, Illinois 61801, United States.|Department of Chemistry, University of Illinois at Urbana-Champaign , Urbana, Illinois 61801, United States.
authors.forename: Eric
authors.initials: E
authors.lastname: Oldfield
authors.affiliation: 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.
authors.forename: Mark
authors.initials: M
authors.lastname: Cushman
authors.affiliation: Department of Comparative Pathobiology, Purdue University College of Veterinary Medicine , West Lafayette, Indiana 47907, United States.|Purdue Institute for Inflammation, Immunology, and Infectious Disease, Purdue University , West Lafayette, Indiana 47907, United States.
authors.forename: Mohamed N
authors.initials: MN
authors.lastname: Seleem
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology*; D017173:Caenorhabditis elegans; D002473:Cell Wall / Q000187:drug effects; D016908:Gram-Positive Bacterial Infections / Q000188:drug therapy* / Q000382:microbiology; D006801:Humans; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D013844:Thiazoles / Q000737:chemistry* / Q000494:pharmacology*; D020713:Vancomycin Resistance; D065507:Vancomycin-Resistant Enterococci / Q000187:drug effects*
chemical_list: D000900:Anti-Bacterial Agents; D013844:Thiazoles