E-BUGS-112 - Methionine Sulfoximine Resistance in Mycobacterium tuberculosis Is Due to a Single Nucleotide Deletion Resulting in Increased Expression of the Major Glutamine Synthetase, GlnA1.
Last updated on 6 September 2011, released on 6 September 2011
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. Trancriptional 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. Data is also available from http://bugs.sgul.ac.uk/E-BUGS-112
transcription profiling by array, compound treatment
BuG@S group <email@example.com>, Simon Waddell
Methionine sulfoximine resistance in Mycobacterium tuberculosis is due to a single nucleotide deletion resulting in increased expression of the major glutamine synthetase, GlnA1. Carroll P, Waddell SJ, Butcher PD, Parish T. Microb Drug Resist 17(3):351-355 (2011), Europe PMC 21875360