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A chemical genetic screen in Mycobacterium tuberculosis identifies carbon-source-dependent growth inhibitors devoid of in vivo efficacy

Author

Listed:
  • Kevin Pethe

    (Novartis Institute for Tropical Diseases, #05-01 Chromos)

  • Patricia C. Sequeira

    (Novartis Institute for Tropical Diseases, #05-01 Chromos)

  • Sanjay Agarwalla

    (Genomics Institute of the Novartis Research Foundation)

  • Kyu Rhee

    (Weill Cornell Medical College)

  • Kelli Kuhen

    (Genomics Institute of the Novartis Research Foundation)

  • Wai Yee Phong

    (Novartis Institute for Tropical Diseases, #05-01 Chromos)

  • Viral Patel

    (Novartis Institute for Tropical Diseases, #05-01 Chromos)

  • David Beer

    (Novartis Institute for Tropical Diseases, #05-01 Chromos)

  • John R. Walker

    (Genomics Institute of the Novartis Research Foundation)

  • Jeyaraj Duraiswamy

    (Novartis Institute for Tropical Diseases, #05-01 Chromos)

  • Jan Jiricek

    (Novartis Institute for Tropical Diseases, #05-01 Chromos)

  • Thomas H. Keller

    (Novartis Institute for Tropical Diseases, #05-01 Chromos)

  • Arnab Chatterjee

    (Genomics Institute of the Novartis Research Foundation)

  • Mai Ping Tan

    (Novartis Institute for Tropical Diseases, #05-01 Chromos
    †Present address: Department of Infection, Immunity and Biochemistry, Cardiff University, Cardiff, UK.)

  • Manjunatha Ujjini

    (Novartis Institute for Tropical Diseases, #05-01 Chromos)

  • Srinivasa P.S. Rao

    (Novartis Institute for Tropical Diseases, #05-01 Chromos)

  • Luis Camacho

    (Novartis Institute for Tropical Diseases, #05-01 Chromos)

  • Pablo Bifani

    (Novartis Institute for Tropical Diseases, #05-01 Chromos)

  • Puiying A. Mak

    (Genomics Institute of the Novartis Research Foundation)

  • Ida Ma

    (Novartis Institute for Tropical Diseases, #05-01 Chromos)

  • S. Whitney Barnes

    (Genomics Institute of the Novartis Research Foundation)

  • Zhong Chen

    (Genomics Institute of the Novartis Research Foundation)

  • David Plouffe

    (Genomics Institute of the Novartis Research Foundation)

  • Pamela Thayalan

    (Novartis Institute for Tropical Diseases, #05-01 Chromos)

  • Seow Hwee Ng

    (Novartis Institute for Tropical Diseases, #05-01 Chromos)

  • Melvin Au

    (Novartis Institute for Tropical Diseases, #05-01 Chromos)

  • Boon Heng Lee

    (Novartis Institute for Tropical Diseases, #05-01 Chromos)

  • Bee Huat Tan

    (Novartis Institute for Tropical Diseases, #05-01 Chromos)

  • Sindhu Ravindran

    (Novartis Institute for Tropical Diseases, #05-01 Chromos)

  • Mahesh Nanjundappa

    (Novartis Institute for Tropical Diseases, #05-01 Chromos)

  • Xiuhua Lin

    (Novartis Institute for Tropical Diseases, #05-01 Chromos)

  • Anne Goh

    (Novartis Institute for Tropical Diseases, #05-01 Chromos)

  • Suresh B. Lakshminarayana

    (Novartis Institute for Tropical Diseases, #05-01 Chromos)

  • Carolyn Shoen

    (Veterans Affairs Medical Center)

  • Michael Cynamon

    (Veterans Affairs Medical Center)

  • Barry Kreiswirth

    (Public Health Research Institute)

  • Veronique Dartois

    (Novartis Institute for Tropical Diseases, #05-01 Chromos)

  • Eric C. Peters

    (Genomics Institute of the Novartis Research Foundation)

  • Richard Glynne

    (Genomics Institute of the Novartis Research Foundation)

  • Sydney Brenner

    (Molecular Engineering Laboratory, Science and Engineering Institute, Agency for Science Technology and Research)

  • Thomas Dick

    (Novartis Institute for Tropical Diseases, #05-01 Chromos)

Abstract

Candidate antibacterials are usually identified on the basis of their in vitro activity. However, the apparent inhibitory activity of new leads can be misleading because most culture media do not reproduce an environment relevant to infection in vivo. In this study, while screening for novel anti-tuberculars, we uncovered how carbon metabolism can affect antimicrobial activity. Novel pyrimidine–imidazoles (PIs) were identified in a whole-cell screen against Mycobacterium tuberculosis. Lead optimization generated in vitro potent derivatives with desirable pharmacokinetic properties, yet without in vivo efficacy. Mechanism of action studies linked the PI activity to glycerol metabolism, which is not relevant for M. tuberculosis during infection. PIs induced self-poisoning of M. tuberculosis by promoting the accumulation of glycerol phosphate and rapid ATP depletion. This study underlines the importance of understanding central bacterial metabolism in vivo and of developing predictive in vitro culture conditions as a prerequisite for the rational discovery of new antibiotics.

Suggested Citation

  • Kevin Pethe & Patricia C. Sequeira & Sanjay Agarwalla & Kyu Rhee & Kelli Kuhen & Wai Yee Phong & Viral Patel & David Beer & John R. Walker & Jeyaraj Duraiswamy & Jan Jiricek & Thomas H. Keller & Arnab, 2010. "A chemical genetic screen in Mycobacterium tuberculosis identifies carbon-source-dependent growth inhibitors devoid of in vivo efficacy," Nature Communications, Nature, vol. 1(1), pages 1-8, December.
    • Handle: RePEc:nat:natcom:v:1:y:2010:i:1:d:10.1038_ncomms1060
    DOI: 10.1038/ncomms1060
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    Cited by:

    1. Nuria Martinez & Lorissa J. Smulan & Michael L. Jameson & Clare M. Smith & Kelly Cavallo & Michelle Bellerose & John Williams & Kim West & Christopher M. Sassetti & Amit Singhal & Hardy Kornfeld, 2023. "Glycerol contributes to tuberculosis susceptibility in male mice with type 2 diabetes," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    2. Irina Gaynanova & James G. Booth & Martin T. Wells, 2016. "Simultaneous Sparse Estimation of Canonical Vectors in the ≫ Setting," Journal of the American Statistical Association, Taylor & Francis Journals, vol. 111(514), pages 696-706, April.

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