oa Editorial [Hot Topic: TB Drug Development (Guest Editor: Courtney C. Aldrich)]

Tuberculosis (TB) remains the second leading cause of infectious disease mortality superseded only by HIV. The etiological agent of TB is Mycobacterium tuberculosis (Mtb), a slow-growing bacillus, which can switch its metabolism to a latent nonreplicating state. The recommended therapy for treatment of TB involves four drugs taken for at least 6 months, referred to as “first-line” drugs due to their high efficacy and relatively low toxicity. These drugs are comprised of isoniazid (first reported in 1951), pyrazinamide (1952), ethambutol (1961), and rifampin (1966). The development of multidrug resistant strains, coupled with the lack of any new antitubercular agents in over four decades, demands the development of new treatment strategies to combat drug resistant TB and to reduce the treatment regimen of susceptible TB strains. In order to put current drug discovery efforts into historical perspective, it should be noted that all of the first-line agents were discovered through phenotypic (i.e. random) screening and subsequent medicinal chemistry optimization. Isoniazid and pyrazinamide are analogs of nicotinamide (vitamin B3) while rifampin is a semisynthetic derivative of the rifamycin polyketide natural products. Ethambutol is a totally synthetic compound based on an ethylenediamine scaffold. The original SAR studies that led to the identification of pyrazinamide and ethambutol were guided solely by efficacy in TB-infected animals, studies that would not be possible now with the increased animal regulations. Surprisingly, the mechanism of action of each of these compounds have only recently been elucidated through advances in molecular genetic techniques of mycobacteria. The genome sequence of M. tuberculosis was published in 1998 providing the first glimpse into the metabolic capacity of this organism. Subsequent studies identified approximately 600 essential genes (at least under the growth conditions evaluated) among the more than 4000 open reading frames. Structural genomic and biochemical efforts have now provided the three dimensional structures and detailed functional characterization of many of these so-called essential gene products. Collectively, these data provide a wealth of information for target-based approaches using rational drug design. Despite the intellectual attractiveness of target-based rational-design, not a single new antibacterial agent has yet been discovered by this approach. Thus classical methods to TB drug discovery, namely phenotypic screening and optimization of known scaffolds, whose mechanism of action may or may not be known, remains a viable approach to discovery of new anti-TB drugs.....