title: Essential roles of methionine and S-adenosylmethionine in the autarkic lifestyle of Mycobacterium tuberculosis.
abstract: Multidrug resistance, strong side effects, and compliance problems in TB chemotherapy mandate new ways to kill Mycobacterium tuberculosis (Mtb). Here we show that deletion of the gene encoding homoserine transacetylase (metA) inactivates methionine and S-adenosylmethionine (SAM) biosynthesis in Mtb and renders this pathogen exquisitely sensitive to killing in immunocompetent or immunocompromised mice, leading to rapid clearance from host tissues. Mtb ΔmetA is unable to proliferate in primary human macrophages, and in vitro starvation leads to extraordinarily rapid killing with no appearance of suppressor mutants. Cell death of Mtb ΔmetA is 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. Mtb ΔmetA could be partially rescued by biotin supplementation, confirming a multitarget cell death mechanism. The work presented here uncovers a previously unidentified vulnerability of Mtb-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.
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461; michael.berney@einstein.yu.edu jacobsw@hhmi.org.
authors.forename: Michael
authors.initials: M
authors.lastname: Berney
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461;
authors.forename: Linda
authors.initials: L
authors.lastname: Berney-Meyer
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461; Shanghai Public Health Clinical Center, Key Laboratory of Medical Molecular Virology at Shanghai Medical College, Fudan University, Shanghai 201508, China;
authors.forename: Ka-Wing
authors.initials: KW
authors.lastname: Wong
authors.affiliation: Howard Hughes Medical Institute, Albert Einstein College of Medicine, Bronx, NY 10461;
authors.forename: Bing
authors.initials: B
authors.lastname: Chen
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461;
authors.forename: Mei
authors.initials: M
authors.lastname: Chen
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461;
authors.forename: John
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Chemistry, Scripps Research Institute, La Jolla, CA 92037;
authors.forename: Jingxin
authors.initials: J
authors.lastname: Wang
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, United Kingdom;
authors.forename: David
authors.initials: D
authors.lastname: Harris
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, United Kingdom;
authors.forename: Julian
authors.initials: J
authors.lastname: Parkhill
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461;
authors.forename: John
authors.initials: J
authors.lastname: Chan
authors.affiliation: California Institute for Biomedical Research, La Jolla, CA 92037.
authors.forename: Feng
authors.initials: F
authors.lastname: Wang
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461; Howard Hughes Medical Institute, Albert Einstein College of Medicine, Bronx, NY 10461; michael.berney@einstein.yu.edu jacobsw@hhmi.org.
authors.forename: William R
authors.initials: WR
authors.lastname: Jacobs
mesh_terms: D000123:Acetyltransferases / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D005260:Female; D006801:Humans; D007121:Immunocompetence / Q000187:drug effects; D055442:Metabolome / Q000187:drug effects; D008715:Methionine / Q000494:pharmacology*; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology / Q000472:pathogenicity / Q000502:physiology*; D012436:S-Adenosylmethionine / Q000494:pharmacology*; D013997:Time Factors; D059467:Transcriptome / Q000187:drug effects / Q000235:genetics; D014774:Virulence
chemical_list: D012436:S-Adenosylmethionine; D008715:Methionine; D000123:Acetyltransferases; C021369:homoserine O-acetyltransferase
keywords: amino acid biosynthesis; bactericidal auxotrophy; host–pathogen interaction; metabolism