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Derailing the aspartate pathway of Mycobacterium tuberculosis to eradicate persistent infection
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Derailing the aspartate pathway of Mycobacterium tuberculosis to eradicate persistent infection
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Journal Article
Derailing the aspartate pathway of Mycobacterium tuberculosis to eradicate persistent infection
2019
Overview
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 pathway at different branch-point enzymes leads to clearance of chronic infections. Together these findings demonstrate that the aspartate pathway in
Mtb
relies on a combination of metabolic control mechanisms, is required for persistence, and represents a target space for anti-tuberculosis drug development.
Amino acid biosynthetic pathways are an attractive alternative to treat chronic infections such as
Mycobacterium tuberculosis
(Mtb). Here, the authors investigate the metabolic response to disruption of the aspartate pathway in persistent Mtb and identify essential enzymes as potential new targets for drug development.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
