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Discovery of a cofactor-independent inhibitor of Mycobacterium tuberculosis InhA.
Xia, Yi; Zhou, Yasheen; Carter, David S; McNeil, Matthew B; Choi, Wai; Halladay, Jason; Berry, Pamela W; Mao, Weimin; Hernandez, Vincent; O'Malley, Theresa; Korkegian, Aaron; Sunde, Bjorn; Flint, Lindsay; Woolhiser, Lisa K; Scherman, Michael S; Gruppo, Veronica; Hastings, Courtney; Robertson, Gregory T; Ioerger, Thomas R; Sacchettini, Jim; Tonge, Peter J; Lenaerts, Anne J; Parish, Tanya; Alley, Mrk.
Afiliação
  • Xia Y; Anacor Pharmaceuticals, Palo Alto, CA, USA.
  • Zhou Y; Anacor Pharmaceuticals, Palo Alto, CA, USA.
  • Carter DS; Anacor Pharmaceuticals, Palo Alto, CA, USA.
  • McNeil MB; TB Discovery Research, Infectious Disease Research Institute, Seattle, WA, USA.
  • Choi W; Anacor Pharmaceuticals, Palo Alto, CA, USA.
  • Halladay J; Anacor Pharmaceuticals, Palo Alto, CA, USA.
  • Berry PW; Anacor Pharmaceuticals, Palo Alto, CA, USA.
  • Mao W; Anacor Pharmaceuticals, Palo Alto, CA, USA.
  • Hernandez V; Anacor Pharmaceuticals, Palo Alto, CA, USA.
  • O'Malley T; TB Discovery Research, Infectious Disease Research Institute, Seattle, WA, USA.
  • Korkegian A; TB Discovery Research, Infectious Disease Research Institute, Seattle, WA, USA.
  • Sunde B; TB Discovery Research, Infectious Disease Research Institute, Seattle, WA, USA.
  • Flint L; TB Discovery Research, Infectious Disease Research Institute, Seattle, WA, USA.
  • Woolhiser LK; Mycobacteria Research Laboratories, Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, CO, USA.
  • Scherman MS; Mycobacteria Research Laboratories, Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, CO, USA.
  • Gruppo V; Mycobacteria Research Laboratories, Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, CO, USA.
  • Hastings C; Mycobacteria Research Laboratories, Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, CO, USA.
  • Robertson GT; Mycobacteria Research Laboratories, Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, CO, USA.
  • Ioerger TR; Texas A&M University, College Station, TX, USA.
  • Sacchettini J; Texas A&M University, College Station, TX, USA.
  • Tonge PJ; Institute of Chemical Biology and Drug Discovery, Departments of Chemistry and Radiology, Stony Brook University, Stony Brook, NY, USA.
  • Lenaerts AJ; Mycobacteria Research Laboratories, Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, CO, USA.
  • Parish T; TB Discovery Research, Infectious Disease Research Institute, Seattle, WA, USA.
  • Alley M; Anacor Pharmaceuticals, Palo Alto, CA, USA.
Life Sci Alliance ; 1(3): e201800025, 2018 Jun.
Article em En | MEDLINE | ID: mdl-30456352
ABSTRACT
New antitubercular agents are needed to combat the spread of multidrug- and extensively drug-resistant strains of Mycobacterium tuberculosis. The frontline antitubercular drug isoniazid (INH) targets the mycobacterial enoyl-ACP reductase, InhA. Resistance to INH is predominantly through mutations affecting the prodrug-activating enzyme KatG. Here, we report the identification of the diazaborines as a new class of direct InhA inhibitors. The lead compound, AN12855, exhibited in vitro bactericidal activity against replicating bacteria and was active against several drug-resistant clinical isolates. Biophysical and structural investigations revealed that AN12855 binds to and inhibits the substrate-binding site of InhA in a cofactor-independent manner. AN12855 showed good drug exposure after i.v. and oral delivery, with 53% oral bioavailability. Delivered orally, AN12855 exhibited dose-dependent efficacy in both an acute and chronic murine model of tuberculosis infection that was comparable with INH. Combined, AN12855 is a promising candidate for the development of new antitubercular agents.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Revista: Life Sci Alliance Ano de publicação: 2018 Tipo de documento: Article País de afiliação: Estados Unidos
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Revista: Life Sci Alliance Ano de publicação: 2018 Tipo de documento: Article País de afiliação: Estados Unidos