Quinolones are one of the few classes of antimicrobial agents that are totally synthetic in origin. The first quinolone, nalidixic acid, was introduced in the 1960s as a narrow-spectrum agent used primarily for the treatment of urinary tract infections. Quinolones possess many desirable attributes for a first-line therapeutic agent against TB. These include potent bactericidal activity against both replicating and non-replicating Mycobacterium tuberculosis (M.tb), favorable long-term safety indicators, oral bioavailability, and an ability to penetrate macrophages. Moxifloxacin, a proven and effective antibacterial agent developed by BayerHealthcare AG, is a third-generation quinolone compound, and has demonstrated effective sterilizing activities against M.tb. The TB Alliance, in collaboration with Bayer, is currently involved in phase III moxifloxacin clinical trials, evaluating the drug as an anti-TB agent with the ability to shorten therapy. However, the quinolone class has not been extensively optimized for a TB indication. In 2003, the TB Alliance initiated a lead identification and optimization project with the goal of identifying a new generation of quinolones with improved efficacy against TB while maintaining safety. Based on data from animal models and the preliminary clinical evaluation of quinolones marketed for other antimicrobial indications, this class of compounds has the potential to be part of a shorter and more effective TB treatment regimen. The objective of the quinolone project is to develop a new generation of DNA gyrase inhibitors that will be effective in shortening TB therapy, while maintaining or improving the safety and tolerability profile. The new agents should also be suitable for the treatment of multidrug-resistant (MDR) TB and TB/HIV co-infections without prohibitive drug-drug interactions with antiretroviral drugs (ARVs) used to treat HIV/AIDS. To achieve these goals, the TB Alliance is collaborating with the Korea Research Institute of Chemical Technology (KRICT) and Yonsei University. Scientists at KRICT have synthesized and tested novel quinolones, and have discovered several promising compounds. Among these, TBK-613 was identified as a preclinical development candidate.