Inhibition of Mycobacterium tuberculosis glutamine synthetase as a novel antibiotic strategy against tuberculosis:: Demonstration of efficacy in vivo
Inhibition of Mycobacterium tuberculosis glutamine synthetase as a novel antibiotic strategy against tuberculosis:: Demonstration of efficacy in vivo
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DOI：
10.1128/iai.71.1.456-464.2003
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发表时间：
2003-01-01
影响因子：
3.1
通讯作者：
Horwitz, MA
中科院分区：
文献类型：
--
作者：
Harth, G;Horwitz, MA
结核病仍然是人类最大的杀手之一，需要新的治疗策略来对抗病原体结核分枝杆菌，它正在迅速对传统抗生素产生抗药性。利用高要求的豚鼠肺结核病模型，我们研究了抑制结核分枝杆菌谷氨酰胺合成酶(GS)作为一种新的抗生素策略的可行性。GS是一种在氮代谢和细胞壁生物合成中发挥关键作用的酶。在气雾剂攻击高毒力结核分枝杆菌Erdman株的豚鼠中，GS抑制剂L-蛋氨酸-SR-亚磺胺(MSO)保护动物防止体重减轻(结核病的标志)，并防止肺和脾中结核分枝杆菌的生长；与对照组动物相比，MSO在攻击后10周使结核分枝杆菌的CFU减少了约0.7个对数单位。MSO与异烟肼在保护动物免受体重减轻和细菌生长方面具有协同作用，使肺和脾中的CFU减少了类似于单独使用异烟肼时的1.5log单位。在抗坏血酸的存在下，MSO非常有效，与对照组动物相比，肺和脾中的CFU减少了2.5个对数单位。本研究表明，抑制结核分枝杆菌GS是一种可行的治疗策略，并支持参与细胞壁生物合成的结核分枝杆菌酶，包括主要分泌蛋白，具有潜在的抗生素靶点的概念。
Tuberculosis remains one of humankind's greatest killers, and new therapeutic strategies are needed to combat the causative agent, Mycobacterium tuberculosis, which is rapidly developing resistance to conventional antibiotics. Using the highly demanding guinea pig model of pulmonary tuberculosis, we have investigated the feasibility of inhibiting M. tuberculosis glutamine synthetase (GS), an enzyme that plays a key role in both nitrogen metabolism and cell wall biosynthesis, as a novel antibiotic strategy. In guinea pigs challenged by aerosol with the highly virulent Erdman strain of M. tuberculosis, the GS inhibitor L-methionine-SR-sulfoximine (MSO) protected the animals against weight loss, a hallmark of tuberculosis, and against the growth of M. tuberculosis in the lungs and spleen; MSO reduced the CFU of M. tuberculosis at 10 weeks after challenge by similar to0.7 log unit compared with that in control animals. MSO acted synergistically with isoniazid in protecting animals against weight loss and bacterial growth, reducing the CFU in the lungs and spleen by similar to1.5 log units below the level seen with isoniazid alone. In the presence of ascorbate, which allows treatment with a higher dose, MSO was highly efficacious, reducing the CFU in the lungs and spleen by 2.5 log units compared with that in control animals. This study demonstrates that inhibition of M. tuberculosis GS is a feasible therapeutic strategy against this pathogen and supports the concept that M. tuberculosis enzymes involved in cell wall biosynthesis, including major secretory proteins, have potential as antibiotic targets.