University of Sussex
Browse
mdr.2010.0125.pdf (242.74 kB)

Methionine sulfoximine resistance in Mycobacterium tuberculosis is due to a single nucleotide deletion resulting in increased expression of the major glutamine synthetase, GlnA1

Download (242.74 kB)
journal contribution
posted on 2023-06-07, 16:07 authored by Paul Carroll, Simon WaddellSimon Waddell, Philip D Butcher, Tanya Parish
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.

History

Publication status

  • Published

File Version

  • Published version

Journal

Microbial Drug Resistance

ISSN

1076-6294

Publisher

Mary Ann Liebert

Issue

3

Volume

17

Page range

351-355

Department affiliated with

  • Clinical and Experimental Medicine Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2012-04-12

First Open Access (FOA) Date

2017-01-10

First Compliant Deposit (FCD) Date

2017-01-10

Usage metrics

    University of Sussex (Publications)

    Categories

    No categories selected

    Exports

    RefWorks
    BibTeX
    Ref. manager
    Endnote
    DataCite
    NLM
    DC