A TB Alliance target-based approach for antibacterial drug discovery (for example, inhibition of a particular enzyme) is one potential strategy toward drug development. A complimentary approach that screens for compounds that inhibit the growth of the organism of interest or a model organism, without any bias toward a particular target, can also be pursued. This program utilizes such an approach.

Translocase 1 (TL1) enzyme is a very attractive target for development of new drugs: • essential for biosynthesis of the peptidoglycan layer of the bacterial cell wall • inhibition leads to cell death • unique to bacteria, absent in eukaryotic cells • no antibiotics on the market targeting TL1.

SQ641 is a chemically-modified analog of nucleoside-based Capuramycin (CM) with a unique mechanism of action and a unique target, the TL-1 enzyme. ATTRIBUTES OF SQ641: It is bactericidal and kills Mtb faster than any existing antitubercular drugs, including isoniazid and rifampin. It is fast-acting, disintegrating even slow-growing bacteria in 24 hours. Is active against all strains of multidrug-resistant clinical strains of Mtb tested to date. Has an exceptional 55 hr post antibiotic effect against Mtb. Shows strong synergy in TB with Ethambutol, Streptomycin, and SQ109.

Sequella synthesized over 100,000 small molecules to discover new scaffolds with anti-microbacterial activity and identify new leads with sufficient in vitro and in vivo activity against M. tuberculosis (Mtb) appropriate pharmacological properties, and suitable toxicity profiles to warrant taking one or more potential new antitubercular drugs into human clinical trials.

Pyrazinamide (PZA) is a first-line drug for the treatment of TB that enabled the shortening of treatment of drug-sensitive TB from 9 to 6 months when it was introduced. PZA is unique among TB drugs that are currently available. It demonstrates impressive sterilizing activity and synergy with other drugs in animal models of TB but its activity itself is not potent against M.tb in a test tube. This phenomenon is not well understood. Further, despite extensive study, its mode of action is not fully understood although activation by an enzyme within the M.tb is required for activity.