Tuberculosis drug discovery in the post-post-genomic era

Authors

  • Benoit Lechartier,

    1. Ecole Polytechnique Fédérale de Lausanne, Global Health Institute, Lausanne, Switzerland
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    • These authors contributed equally to this work.
  • Jan Rybniker,

    1. Ecole Polytechnique Fédérale de Lausanne, Global Health Institute, Lausanne, Switzerland
    2. 1st Department of Internal Medicine, University of Cologne, Cologne, Germany
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    • These authors contributed equally to this work.
  • Alimuddin Zumla,

    1. Division of Infection and Immunity, University College London and UCLHospitals NHS Foundation Trust, London, UK
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  • Stewart T Cole

    Corresponding author
    1. Ecole Polytechnique Fédérale de Lausanne, Global Health Institute, Lausanne, Switzerland
    • Corresponding author. Tel: +41 21 693 1851; Fax: +41 21 693 1790; E-mail: stewart.cole@epfl.ch

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Abstract

The expectation that genomics would result in new therapeutic interventions for infectious diseases remains unfulfilled. In the post-genomic era, the decade immediately following the availability of the genome sequence of Mycobacterium tuberculosis, tuberculosis (TB) drug discovery relied heavily on the target-based approach but this proved unsuccessful leading to a return to whole cell screening. Genomics underpinned screening by providing knowledge and many enabling technologies, most importantly whole genome resequencing to find resistance mutations and targets, and this resulted in a selection of leads and new TB drug candidates that are reviewed here. Unexpectedly, many new targets were found to be ‘promiscuous’ as they were inhibited by a variety of different compounds. In the post-post-genomics era, more advanced technologies have been implemented and these include high-content screening, screening for inhibitors of latency, the use of conditional knock-down mutants for validated targets and siRNA screens. In addition, immunomodulation and pharmacological manipulation of host functions are being explored in an attempt to widen our therapeutic options.

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