Derailing the aspartate pathway of Mycobacterium tuberculosis to eradicate persistent infection

Erik J. Hasenoehrl, Dannah Rae Sajorda, Linda Berney-Meyer, Samantha Johnson, Jo Ann M. Tufariello, Tobias Fuhrer, Gregory M. Cook, William R. Jacobs, Michael Berney

Research output: Contribution to journalArticle

3 Scopus citations

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 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.

Original languageEnglish (US)
Article number4215
JournalNature communications
Volume10
Issue number1
DOIs
StatePublished - Dec 1 2019

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Hasenoehrl, E. J., Rae Sajorda, D., Berney-Meyer, L., Johnson, S., Tufariello, J. A. M., Fuhrer, T., Cook, G. M., Jacobs, W. R., & Berney, M. (2019). Derailing the aspartate pathway of Mycobacterium tuberculosis to eradicate persistent infection. Nature communications, 10(1), [4215]. https://doi.org/10.1038/s41467-019-12224-3