New antitubercular agents that act through previously unexploited mechanisms are urgently needed. Here, we employed a drug repurposing platform to identify hit TI-374 with sub-micromolar potency against Mycobacterium tuberculosis (Mtb). Resistance mutation mapping, supplementation assays, and direct biochemical studies revealed that TI-374 exerts its anti-tubercular activity by irreversibly inhibiting the enzyme alanine aminotransferase (AlaA, encoded by Rv0337c), leading to alanine auxotrophy. TI-374 was modified to yield TI-801, which inhibits Mtb with low-nanomolar potency through inhibition of AlaA. Both compounds remained active against intracellular Mtb in an ex vivo macrophage model despite excess endogenous alanine, suggesting that Mtb cannot scavenge alanine from the host. Genetic deletion of alaA results in attenuated bacterial survival in a murine infection model. Together, these findings position Mtb AlaA as a host-relevant metabolic vulnerability and highlight TI-801 as a promising scaffold for the development of antitubercular agents with a novel mechanism of action.
Shalaby, M.-A. W., Beeralingappa, N. C., Shrinidhi, A., Makafe, G. G., Nece, E., Patwardhan, A., Low-Beer, T., Kuki, A., Sheinerman, F., Weinrick, B., Flaherty, D. P., Chojnacki, M.
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