Antituberculosis thiophenes define a requirement for Pks13 in mycolic acid biosynthesis

Regina Wilson; Pradeep Kumar; Vijay Parashar; Catherine Vilchèze; Romain Veyron-Churlet; Joel S Freundlich; S. Whitney Barnes; John R Walker; Michael J Szymonifka; Emily Marchiano; Shubhada Shenai; Roberto Colangeli; William R Jacobs; Matthew B Neiditch; Laurent Kremer; David Alland

doi:10.1038/nchembio.1277

Back

Antituberculosis thiophenes define a requirement for Pks13 in mycolic acid biosynthesis

Journal article

Open access

Peer reviewed

Antituberculosis thiophenes define a requirement for Pks13 in mycolic acid biosynthesis

Regina Wilson, Pradeep Kumar, Vijay Parashar, Catherine Vilchèze, Romain Veyron-Churlet, Joel S Freundlich, S. Whitney Barnes, John R Walker, Michael J Szymonifka, Emily Marchiano, …

Nature chemical biology, Vol.9(8), pp.499-506

08/2013

DOI: https://doi.org/10.1038/nchembio.1277

PMCID: PMC3720791

PMID: 23770708

Abstract

We report a new class of thiophene (TP) compounds that kill Mycobacterium tuberculosis ( Mtb ) by the novel mechanism of Pks13 inhibition. An F79S mutation near the catalytic Ser-55 site in Pks13 conferred TP-resistance in Mtb . Over-expression of wild-type pks13 resulted in TP-resistance and over-expression of the F79S pks13 mutant conferred high-level resistance. In vitro , TP inhibited fatty acyl-AMP loading onto Pks13. TP inhibited mycolic acid biosynthesis in wild-type Mtb , but to a much lesser extent in TP-resistant Mtb . TP treatment was bactericidal and equivalent to the first-line drug isoniazid, but it was less likely to permit emergent resistance. Combined isoniazid and TP treatment exhibited sterilizing activity. Computational-docking identified a possible TP-binding groove within the Pks13 ACP domain. This study confirms that Mtb Pks13 is required for mycolic acid biosynthesis, validates it as a druggable target and demonstrates the therapeutic potential of simultaneously inhibiting multiple targets in the same biosynthetic pathway.

Files and links (1)

url

https://doi.org/10.1038/nchembio.1277View

Version of Record (VoR) Open

Metrics

20 Record Views

115 Times Cited - Web of Science

See more details

Details

Title: Antituberculosis thiophenes define a requirement for Pks13 in mycolic acid biosynthesis
Creators: Regina Wilson - Division of Infectious Disease, Department of Medicine, and the Ruy V. Lourenco Center for the Study of Emerging and Reemerging Pathogens, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, NJ, USA
Pradeep Kumar - Division of Infectious Disease, Department of Medicine, and the Ruy V. Lourenco Center for the Study of Emerging and Reemerging Pathogens, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, NJ, USA
Vijay Parashar - Department of Microbiology and Molecular Genetics, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, USA
Catherine Vilchèze - Howard Hughes Medical Institute, Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA
Romain Veyron-Churlet - Laboratoire de Dynamique des Interactions Membranaires Normales et Pathologiques, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5235, Université de Montpellier 2, 34095 Montpellier Cedex 5, France
Joel S Freundlich - Department of Pharmacology & Physiology, Department of Medicine, and the Ruy V. Lourenco Center for the Study of Emerging and Reemerging Pathogens, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, NJ, USA
S. Whitney Barnes - Genomics Institute of the Novartis Research Foundation, San Diego, California, USA
John R Walker - Genomics Institute of the Novartis Research Foundation, San Diego, California, USA
Michael J Szymonifka - Department of Pharmacology & Physiology, Department of Medicine, and the Ruy V. Lourenco Center for the Study of Emerging and Reemerging Pathogens, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, NJ, USA
Emily Marchiano - Division of Infectious Disease, Department of Medicine, and the Ruy V. Lourenco Center for the Study of Emerging and Reemerging Pathogens, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, NJ, USA
Shubhada Shenai - Division of Infectious Disease, Department of Medicine, and the Ruy V. Lourenco Center for the Study of Emerging and Reemerging Pathogens, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, NJ, USA
Roberto Colangeli - Division of Infectious Disease, Department of Medicine, and the Ruy V. Lourenco Center for the Study of Emerging and Reemerging Pathogens, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, NJ, USA
William R Jacobs - Howard Hughes Medical Institute, Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA
Matthew B Neiditch - Department of Microbiology and Molecular Genetics, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, USA
Laurent Kremer - Laboratoire de Dynamique des Interactions Membranaires Normales et Pathologiques, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5235, Université de Montpellier 2, 34095 Montpellier Cedex 5, France
David Alland - Division of Infectious Disease, Department of Medicine, and the Ruy V. Lourenco Center for the Study of Emerging and Reemerging Pathogens, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, NJ, USA
Publication Details: Nature chemical biology, Vol.9(8), pp.499-506
Date published: 08/2013
Academic Unit: Medicinal Chemistry (EMSOP); Microbiology, Biochemistry and Molecular Genetics (NJMS); Pharmacology (NJMS); Medicine - Infectious Diseases (NJMS)
Language: English
Resource Type: Journal article
Identifiers: 991031654506004646