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Tuberculosis (TB) is the 2nd leading cause of death by infectious disease in adults worldwide and it is estimated that one third of the world’s population is infected with Mycobacterium tuberculosis (Mtb). Intrinsic drug resistance of Mtb limits the use of most highly effective antibiotics that are already on the market. This project has identified a number of synergistic combinations of known drugs capable of inhibiting Mtb growth in vitro and within macrophages and a lead combination has been taken forward into in vivo proof of concept studies to show the utility of the synergistic combination in mouse models of TB. Studies performed to date have included formulation, pharmacokinetic and dose range finding/tolerability studies of the drugs alone, and in combination. Unfortunately, while initial efficacy studies did not show improved activity of the combination in infected mice, pharmacokinetic studies have offered insight into a possible cause for the lack of activity.