Drugs versus bugs: in pursuit of the persistent predator Mycobacterium tuberculosis

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Abstract
The global tuberculosis (TB) epidemic has not dwindled but has actually grown, largely owing to the challenges that are presented by persistence and resistance. Huge advances in therapeutic regimens are needed to dramatically reduce the course of treatment from months to days. To realize the vulnerabilities of Mycobacterium tuberculosis, genetic methods are being applied to identify genes that are essential to the various metabolic states that are believed to be pertinent to both the establishment and maintenance of infection. The respective essential gene products are being explored using industry-validated drug-discovery methods to produce potential drug candidates. High-throughput virtual and biochemical screening efforts are described, in addition to 'lower-throughput' structure-based designs. Antituberculars in clinical trials are discussed in terms of their respective modes of action and relative strengths and weaknesses as compared with current treatment modalities. A select number of non-TB-approved drugs are described with regard to their potential for being applied as antituberculars. The list includes anti-infectives, such as linezolid and, perhaps surprisingly to some, anti-psychotics, such as the phenothiazine family. Owing to the identification of the gene products that are essential to persistence and their new small-molecule inhibitors, which are fast acting and unencumbered by resistance, scientists may yet be able to realize the lofty goals that have been set for new antitubercular therapies.