Tuberculosis (TB) caused by Mycobacterium tuberculosis remains a leading cause of mortality worldwide into 21st century. The mortality and spread of this disease has further been aggravated because of synergy of this disease with HIV. A number of anti-TB drugs are ineffective against this disease because of development of resistance strains. Internationally efforts are being made to develop new anti-tubercular agents. A number of drug targets from cell wall biosynthesis, nucleic acid biosynthesis, and many other biosynthetic pathways are being unraveled throughout the world and are being utilized for drug development. In this review, socioeconomic problems in developing countries, efforts to control this disease in different individuals, the targets (known already and newly discovered), existing anti-tubercular agents including natural products and lead molecules, and the future prospects to develop new anti-TB agents are described.

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DNA ligases utilize either ATP or NAD؉ as cofactors to catalyze the formation of phosphodiester bonds in nicked DNA. Those utilizing NAD ؉ are attractive drug targets because of the unique cofactor requirement for ligase activity. We report here the crystal structure of the adenylation domain of the Mycobacterium tuberculosis NAD ؉ -dependent ligase with bound AMP. The adenosine nucleoside moiety of AMP adopts a syn-conformation. The structure also captures a new spatial disposition between the two subdomains of the adenylation domain. Based on the crystal structure and an in-house compound library, we have identified a novel class of inhibitors for the enzyme using in silico docking calculations. The glycosyl ureide-based inhibitors were able to distinguish between NAD ؉ -and ATP-dependent ligases as evidenced by in vitro assays using T4 ligase and human DNA ligase I. Moreover, assays involving an Escherichia coli strain harboring a temperature-sensitive ligase mutant and a ligase-deficient Salmonella typhimurium strain suggested that the bactericidal activity of the inhibitors is due to inhibition of the essential ligase enzyme. The results can be used as the basis for rational design of novel antibacterial agents.DNA ligases are vital enzymes in replication and repair and catalyze the formation of a phosphodiester linkage between adjacent termini in double-stranded DNA through similar mechanisms (1). These enzymes can be divided into two classes, viz. NAD ؉ -and ATP-dependent ligases, based on the cofactor specificities (2). NAD ؉ -dependent DNA ligases, commonly called LigA, are found in bacteria and entomopoxviruses (3, 20), whereas ATP-dependent ligases are ubiquitous (3). Although there is little sequence homology between the eubacterial and eukaryotic enzymes, they exhibit some structural homology in specific domains (4, 5). The mechanistic steps involved in enzymatic action are also broadly conserved. Briefly, in the first step, the mode of action involves an attack on the ␣-phosphorus of ATP or NAD ؉ by the enzyme, releasing pyrophosphate or NMN and forming a ligase-adenylate intermediate. In the second step, the bound AMP is transferred to the 5Ј-end of DNA to form a DNAadenylate intermediate. AMP is released in the third step, where the protein catalyzes the joining of the 3Ј-nicked DNA to the DNA-adenylate intermediate. These steps involve large conformational changes and also encircling and partial unwinding of the nicked DNA substrate (6 -8).Some bacteria code for both NAD ؉ -and ATP-dependent DNA ligases (3, 9). Mycobacterium tuberculosis codes for at least three different types of ATP-dependent ligases and a NAD ϩ -dependent ligase (10, 11). Gene knockout and other studies have shown LigA to be indispensable in several bacteria, including Escherichia coli, Staphylococcus aureus, Bacillus subtilis, and M. tuberculosis (10,(12)(13)(14)(15).No LigA structure from mycobacterial sources is available to date. However, the crystal structure of the full-length protein is available for the Thermus filifo...

New and better drugs are needed for tuberculosis (TB), particularly for the multi-drug resistant (MDR) disease. However, the highly infectious nature of MDR Mycobacterium tuberculosis restricts its use for large scale screening of probable drug candidates. We have evaluated the potential of a screen based on a 'fast grower' mycobacterium to shortlist compounds which could be active against MDR M. tuberculosis. Sensitivity profiles of M. smegmatis, M. phlei and M. fortuitum as well as MDR clinical isolates of M. tuberculosis were determined against anti-TB drugs isoniazid and rifampicin. Among the three fast growers, M. smegmatis was found to display a profile similar to MDR M. tuberculosis. Subsequently we evaluated the performance of M. smegmatis as a 'surrogate' screen for 120 compounds which were synthesized for anti-TB activity. Fifty of these molecules were active against M. tuberculosis H(37)Rv at a minimum inhibitory concentration (MIC) cutoff of