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Lysyl-tRNA synthetase, a target for urgently needed M. tuberculosis drugs

Author

Listed:
  • Simon R. Green

    (University of Dundee)

  • Susan H. Davis

    (University of Dundee)

  • Sebastian Damerow

    (University of Dundee)

  • Curtis A. Engelhart

    (Weill Cornell Medical College)

  • Michael Mathieson

    (University of Dundee)

  • Beatriz Baragaña

    (University of Dundee)

  • David A. Robinson

    (University of Dundee)

  • Jevgenia Tamjar

    (University of Dundee)

  • Alice Dawson

    (University of Dundee)

  • Fabio K. Tamaki

    (University of Dundee)

  • Kirsteen I. Buchanan

    (University of Dundee)

  • John Post

    (University of Dundee)

  • Karen Dowers

    (University of Dundee)

  • Sharon M. Shepherd

    (University of Dundee)

  • Chimed Jansen

    (University of Dundee)

  • Fabio Zuccotto

    (University of Dundee)

  • Ian H. Gilbert

    (University of Dundee)

  • Ola Epemolu

    (University of Dundee)

  • Jennifer Riley

    (University of Dundee)

  • Laste Stojanovski

    (University of Dundee)

  • Maria Osuna-Cabello

    (University of Dundee)

  • Esther Pérez-Herrán

    (GlaxoSmithKline)

  • María José Rebollo

    (GlaxoSmithKline)

  • Laura Guijarro López

    (GlaxoSmithKline)

  • Patricia Casado Castro

    (GlaxoSmithKline)

  • Isabel Camino

    (GlaxoSmithKline)

  • Heather C. Kim

    (Weill Cornell Medical College)

  • James M. Bean

    (Memorial Sloan Kettering Cancer Center)

  • Navid Nahiyaan

    (Weill Cornell Medical College)

  • Kyu Y. Rhee

    (Weill Cornell Medical College)

  • Qinglan Wang

    (Laboratory of Clinical Immunology and Microbiology, NIAID, NIH)

  • Vee Y. Tan

    (Laboratory of Clinical Immunology and Microbiology, NIAID, NIH)

  • Helena I. M. Boshoff

    (Laboratory of Clinical Immunology and Microbiology, NIAID, NIH)

  • Paul J. Converse

    (Johns Hopkins University, School of Medicine)

  • Si-Yang Li

    (Johns Hopkins University, School of Medicine)

  • Yong S. Chang

    (Johns Hopkins University, School of Medicine)

  • Nader Fotouhi

    (Global Alliance for TB Drug Development)

  • Anna M. Upton

    (Global Alliance for TB Drug Development)

  • Eric L. Nuermberger

    (Johns Hopkins University, School of Medicine)

  • Dirk Schnappinger

    (Weill Cornell Medical College)

  • Kevin D. Read

    (University of Dundee)

  • Lourdes Encinas

    (GlaxoSmithKline)

  • Robert H. Bates

    (GlaxoSmithKline)

  • Paul G. Wyatt

    (University of Dundee)

  • Laura A. T. Cleghorn

    (University of Dundee)

Abstract

Tuberculosis is a major global cause of both mortality and financial burden mainly in low and middle-income countries. Given the significant and ongoing rise of drug-resistant strains of Mycobacterium tuberculosis within the clinical setting, there is an urgent need for the development of new, safe and effective treatments. Here the development of a drug-like series based on a fused dihydropyrrolidino-pyrimidine scaffold is described. The series has been developed against M. tuberculosis lysyl-tRNA synthetase (LysRS) and cellular studies support this mechanism of action. DDD02049209, the lead compound, is efficacious in mouse models of acute and chronic tuberculosis and has suitable physicochemical, pharmacokinetic properties and an in vitro safety profile that supports further development. Importantly, preliminary analysis using clinical resistant strains shows no pre-existing clinical resistance towards this scaffold.

Suggested Citation

  • Simon R. Green & Susan H. Davis & Sebastian Damerow & Curtis A. Engelhart & Michael Mathieson & Beatriz Baragaña & David A. Robinson & Jevgenia Tamjar & Alice Dawson & Fabio K. Tamaki & Kirsteen I. Bu, 2022. "Lysyl-tRNA synthetase, a target for urgently needed M. tuberculosis drugs," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33736-5
    DOI: 10.1038/s41467-022-33736-5
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    References listed on IDEAS

    as
    1. Madhumitha Nandakumar & Carl Nathan & Kyu Y. Rhee, 2014. "Isocitrate lyase mediates broad antibiotic tolerance in Mycobacterium tuberculosis," Nature Communications, Nature, vol. 5(1), pages 1-10, September.
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    Cited by:

    1. Di Qu & Peng Ge & Laure Botella & Sae Woong Park & Ha-Na Lee & Natalie Thornton & James M. Bean & Inna V. Krieger & James C. Sacchettini & Sabine Ehrt & Courtney C. Aldrich & Dirk Schnappinger, 2024. "Mycobacterial biotin synthases require an auxiliary protein to convert dethiobiotin into biotin," Nature Communications, Nature, vol. 15(1), pages 1-11, December.

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