Mycobacterium tuberculosis (M.tb) is able to maintain infection within its human host by replicating within macrophages. M.tb does this by employing specific metabolic pathways to utilize host-derived nutrients (such as fatty acids and cholesterol) for energy production under a nutritionally-constrained environment. To identify a novel set of potential drug candidates, TB Alliance is screening libraries of small molecules against M.tb-infected human macrophages to identify novel agents which are potent against M.tb residing within macrophages.

Hits have been identified against M. tb Rho Kinase through screening of the GSK compound library. The compounds are active in the Rho enzymatic assays.

A new series has been identified with excellent potency in macrophages and in cholesterol medium. The series is currently being optimized for pharmacokinetic properties and efficacy to identify a preclinical candidate with Evotec.