Design and Development of Mycobacterium tuberculosis Lysine ɛ‐Aminotransferase Inhibitors for Latent Tuberculosis Infection

Lysine ?‐aminotransferase (LAT) is a protein involved in lysine catabolism, and it plays a significant role during the persistent/latent phase of Mycobacterium tuberculosis (MTB), as observed by its up‐regulation by ~40‐fold during this stage. We have used the crystal structure of MTB LAT in external aldimine form in complex with its substrate lysine as a template to design and identify seven lead compounds with IC₅₀ ranging from 18.06 to > 90 μm . We have synthesized 21 compounds based on the identified lead, and compound 21 [2,2′‐oxybis(N′‐(4‐fluorobenzylidene)acetohydrazide)] was found to be the most active with MTB LAT IC₅₀ of 0.81 ± 0.03 μm . Compound 21 also showed a 2.3 log reduction in the nutrient‐starved MTB model and was more potent than standard isoniazid and rifampicin at the same dose level of 10 μg/mL.