BRD4592

BRD4592A is a synthetic azetidine derivative discovered by whole cell screening that kills Mycobacterium tuberculosis (Mtb) through allosteric inhibition of tryptophan synthase (TrpAB). It binds at the TrpAB a–b-subunit interface and affects multiple steps in the enzyme’s overall reaction resulting in bactericidal activity.  It is active in zebrafish, but has metabolic liabilities including rapid mouse liver microsome clearance that preclude its efficacy testing in a mouse model.  The Mtb TrpAB gene is essential in vivo.