title: Methionine sulfoximine resistance in Mycobacterium tuberculosis is due to a single nucleotide deletion resulting in increased expression of the major glutamine synthetase, GlnA1.
abstract: We investigated the effect of methionine sulfoximine (MetSox), a potent inhibitor of glutamine synthetase, on Mycobacterium tuberculosis. M. tuberculosis encodes four glutamine synthetases, of which MetSox targets the type I enzyme encoded by glnA1. Transcriptional profiling revealed that glutamate synthetase (gltB) and a type II glutamine synthetase (glnA3) were induced after exposure to MetSox. In addition, we observed a high rate (10(-5)) of spontaneous resistance to MetSox. All resistant strains had a single-nucleotide deletion in the 5' region of glnA1, and Western analysis revealed that GlnA1 expression was increased in resistant as compared with sensitive strains. These data show that M. tuberculosis can respond to the effect of MetSox inhibition either by up-regulation of GlnA3 or by GlnA1. The high frequency of resistance suggests that MetSox and other compounds specifically targeting GlnA1 are not likely to become successful anti-mycobacterial agents.
authors.affiliation: Barts & The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
authors.forename: Paul
authors.initials: P
authors.lastname: Carroll
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Waddell
authors.forename: Philip D
authors.initials: PD
authors.lastname: Butcher
authors.forename: Tanya
authors.initials: T
authors.lastname: Parish
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001426:Bacterial Proteins / Q000235:genetics; D024881:Drug Resistance, Bacterial; D053263:Gene Regulatory Networks / Q000187:drug effects; D005974:Glutamate-Ammonia Ligase / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D008717:Methionine Sulfoximine / Q000494:pharmacology*; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics*; D017384:Sequence Deletion; D015854:Up-Regulation
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D008717:Methionine Sulfoximine; C081173:glutamine synthetase I; D005974:Glutamate-Ammonia Ligase