Essential roles of methionine andS-adenosylmethionine in the autarkic lifestyle ofMycobacterium tuberculosis

Author:

Berney Michael,Berney-Meyer Linda,Wong Ka-Wing,Chen Bing,Chen Mei,Kim John,Wang Jingxin,Harris David,Parkhill Julian,Chan John,Wang Feng,Jacobs William R.

Abstract

Multidrug resistance, strong side effects, and compliance problems in TB chemotherapy mandate new ways to killMycobacterium tuberculosis(Mtb). Here we show that deletion of the gene encoding homoserine transacetylase (metA) inactivates methionine andS-adenosylmethionine (SAM) biosynthesis inMtband renders this pathogen exquisitely sensitive to killing in immunocompetent or immunocompromised mice, leading to rapid clearance from host tissues.MtbΔmetAis unable to proliferate in primary human macrophages, and in vitro starvation leads to extraordinarily rapid killing with no appearance of suppressor mutants. Cell death ofMtbΔmetAis faster than that of other auxotrophic mutants (i.e., tryptophan, pantothenate, leucine, biotin), suggesting a particularly potent mechanism of killing. Time-course metabolomics showed complete depletion of intracellular methionine and SAM. SAM depletion was consistent with a significant decrease in methylation at the DNA level (measured by single-molecule real-time sequencing) and with the induction of several essential methyltransferases involved in biotin and menaquinone biosynthesis, both of which are vital biological processes and validated targets of antimycobacterial drugs.MtbΔmetAcould be partially rescued by biotin supplementation, confirming a multitarget cell death mechanism. The work presented here uncovers a previously unidentified vulnerability ofMtb—the incapacity to scavenge intermediates of SAM and methionine biosynthesis from the host. This vulnerability unveils an entirely new drug target space with the promise of rapid killing of the tubercle bacillus by a new mechanism of action.

Funder

HHS | NIH | National Institute of Allergy and Infectious Diseases

Bill and Melinda Gates Foundation

Wellcome Trust

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

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