结核分枝杆菌中亚精氨酸琥珀酸亚胺抗性是由于单个核苷酸缺失导致主要谷氨酰胺合成酶 GlnA1 表达增加所致。
Methionine sulfoximine resistance in Mycobacterium tuberculosis is due to a single nucleotide deletion resulting in increased expression of the major glutamine synthetase, GlnA1.
机构信息
Barts & The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
出版信息
Microb Drug Resist. 2011 Sep;17(3):351-5. doi: 10.1089/mdr.2010.0125.
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.
摘要
我们研究了蛋氨酸亚砜（MetSox）对结核分枝杆菌的影响。结核分枝杆菌编码四种谷氨酰胺合成酶，MetSox 靶向 glnA1 编码的 I 型酶。转录谱分析显示，暴露于 MetSox 后谷氨酸合成酶（gltB）和 II 型谷氨酰胺合成酶（glnA3）被诱导。此外，我们观察到对 MetSox 的自发耐药率很高（10(-5)）。所有耐药株在 glnA1 的 5'区域都有一个单核苷酸缺失，Western 分析显示耐药株中 GlnA1 的表达高于敏感株。这些数据表明，结核分枝杆菌可以通过上调 GlnA3 或 GlnA1 来应对 MetSox 抑制的影响。高耐药率表明 MetSox 和其他专门针对 GlnA1 的化合物不太可能成为成功的抗分枝杆菌药物。
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