Derailing the aspartate pathway of Mycobacterium tuberculosis to eradicate persistent infection.

ABSTRACT: A major constraint for developing new anti-tuberculosis drugs is the limited number of validated targets that allow eradication of persistent infections. Here, we uncover a vulnerable component of Mycobacterium tuberculosis (Mtb) persistence metabolism, the aspartate pathway. Rapid death of threonine and homoserine auxotrophs points to a distinct susceptibility of Mtb to inhibition of this pathway. Combinatorial metabolomic and transcriptomic analysis reveals that inability to produce threonine leads to deregulation of aspartate kinase, causing flux imbalance and lysine and DAP accumulation. Mtb's adaptive response to this metabolic stress involves a relief valve-like mechanism combining lysine export and catabolism via aminoadipate. We present evidence that inhibition of the aspartate pat

SUBMITTER: Hasenoehrl EJ 

PROVIDER: S-EPMC6746716 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature