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EMBO Mol Med. 2014 Feb;6(2):158-68. doi: 10.1002/emmm.201201772. Epub 2014 Jan 8.

Tuberculosis drug discovery in the post-post-genomic era.

Author information

1
Ecole Polytechnique Fédérale de Lausanne Global Health Institute, Lausanne, Switzerland.

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.

PMID:
24401837
PMCID:
PMC3927952
DOI:
10.1002/emmm.201201772
[Indexed for MEDLINE]
Free PMC Article

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