Your browser doesn't support javascript.
loading
Development of a Novel Lead that Targets M. tuberculosis Polyketide Synthase 13.
Aggarwal, Anup; Parai, Maloy K; Shetty, Nishant; Wallis, Deeann; Woolhiser, Lisa; Hastings, Courtney; Dutta, Noton K; Galaviz, Stacy; Dhakal, Ramesh C; Shrestha, Rupesh; Wakabayashi, Shoko; Walpole, Chris; Matthews, David; Floyd, David; Scullion, Paul; Riley, Jennifer; Epemolu, Ola; Norval, Suzanne; Snavely, Thomas; Robertson, Gregory T; Rubin, Eric J; Ioerger, Thomas R; Sirgel, Frik A; van der Merwe, Ruben; van Helden, Paul D; Keller, Peter; Böttger, Erik C; Karakousis, Petros C; Lenaerts, Anne J; Sacchettini, James C.
Afiliação
  • Aggarwal A; Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX, USA.
  • Parai MK; Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX, USA.
  • Shetty N; Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX, USA.
  • Wallis D; Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX, USA.
  • Woolhiser L; 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.
  • Dutta NK; Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Galaviz S; Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX, USA.
  • Dhakal RC; Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX, USA.
  • Shrestha R; Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX, USA.
  • Wakabayashi S; Department of Immunology and Infectious Disease, Harvard T. H. Chan School of Public Health, Boston, MA, USA.
  • Walpole C; Structure-guided Drug Discovery Coalition, SGC Toronto, ON, Canada.
  • Matthews D; Structure-guided Drug Discovery Coalition, SGC Toronto, ON, Canada.
  • Floyd D; Structure-guided Drug Discovery Coalition, SGC Toronto, ON, Canada.
  • Scullion P; Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee, UK.
  • Riley J; Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee, UK.
  • Epemolu O; Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee, UK.
  • Norval S; Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee, UK.
  • Snavely T; Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX, USA.
  • Robertson GT; Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO, USA.
  • Rubin EJ; Department of Immunology and Infectious Disease, Harvard T. H. Chan School of Public Health, Boston, MA, USA.
  • Ioerger TR; Department of Computer Science and Engineering, Texas A&M University, College Station, TX, USA.
  • Sirgel FA; NRF Centre of Excellence for Biomedical TB Research and the South African MRC Centre for Molecular and Cellular Biology, Division of Molecular Biology and Human Genetics, Stellenbosch University, Tygerberg, South Africa.
  • van der Merwe R; NRF Centre of Excellence for Biomedical TB Research and the South African MRC Centre for Molecular and Cellular Biology, Division of Molecular Biology and Human Genetics, Stellenbosch University, Tygerberg, South Africa.
  • van Helden PD; NRF Centre of Excellence for Biomedical TB Research and the South African MRC Centre for Molecular and Cellular Biology, Division of Molecular Biology and Human Genetics, Stellenbosch University, Tygerberg, South Africa.
  • Keller P; Institute of Medical Microbiology, National Center for Mycobacteria, University of Zurich, Zurich, Switzerland.
  • Böttger EC; Institute of Medical Microbiology, National Center for Mycobacteria, University of Zurich, Zurich, Switzerland.
  • Karakousis PC; Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Lenaerts AJ; Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO, USA.
  • Sacchettini JC; Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX, USA. Electronic address: sacchett@tamu.edu.
Cell ; 170(2): 249-259.e25, 2017 Jul 13.
Article em En | MEDLINE | ID: mdl-28669536
ABSTRACT
Widespread resistance to first-line TB drugs is a major problem that will likely only be resolved through the development of new drugs with novel mechanisms of action. We have used structure-guided methods to develop a lead molecule that targets the thioesterase activity of polyketide synthase Pks13, an essential enzyme that forms mycolic acids, required for the cell wall of Mycobacterium tuberculosis. Our lead, TAM16, is a benzofuran class inhibitor of Pks13 with highly potent in vitro bactericidal activity against drug-susceptible and drug-resistant clinical isolates of M. tuberculosis. In multiple mouse models of TB infection, TAM16 showed in vivo efficacy equal to the first-line TB drug isoniazid, both as a monotherapy and in combination therapy with rifampicin. TAM16 has excellent pharmacological and safety profiles, and the frequency of resistance for TAM16 is ∼100-fold lower than INH, suggesting that it can be developed as a new antitubercular aimed at the acute infection. PAPERCLIP.
Assuntos
Palavras-chave
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Piperidinas / Tuberculose / Benzofuranos / Desenho de Fármacos / Farmacorresistência Bacteriana / Mycobacterium tuberculosis / Antituberculosos Limite: Animals Idioma: En Revista: Cell Ano de publicação: 2017 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 Assunto principal: Piperidinas / Tuberculose / Benzofuranos / Desenho de Fármacos / Farmacorresistência Bacteriana / Mycobacterium tuberculosis / Antituberculosos Limite: Animals Idioma: En Revista: Cell Ano de publicação: 2017 Tipo de documento: Article País de afiliação: Estados Unidos