title: Tuberculosis drug discovery in the post-post-genomic era.
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.
authors.affiliation: Ecole Polytechnique Fédérale de Lausanne Global Health Institute, Lausanne, Switzerland.
authors.forename: Benoit
authors.initials: B
authors.lastname: Lechartier
authors.forename: Jan
authors.initials: J
authors.lastname: Rybniker
authors.forename: Alimuddin
authors.initials: A
authors.lastname: Zumla
authors.forename: Stewart T
authors.initials: ST
authors.lastname: Cole
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000494:pharmacology / Q000627:therapeutic use*; D055808:Drug Discovery; D023281:Genomics; D014943:Global Health; D054884:Host-Pathogen Interactions / Q000187:drug effects; D006801:Humans; D014376:Tuberculosis / Q000175:diagnosis / Q000188:drug therapy*
chemical_list: D000995:Antitubercular Agents