Tuberculosis drug discovery in the post‐post‐genomic era

EMBO Molecular Medicine

Benoit Lechartier¹  Jan Rybniker¹  Alimuddin Zumla² 

[1] Ecole Polytechnique Fédérale de Lausanne, Global Health Institute, Lausanne, Switzerland;Division of Infection and Immunity, University College London and UCLHospitals NHS Foundation Trust, London, UK

关键词: drug candidates;    drug discovery;    genomics;    screening;    tuberculosis;   

DOI  :  10.1002/emmm.201201772

来源: Wiley

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2014 The Authors.

Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.