Mycobacterium tuberculosis isocitrate lyases 1 and 2 are jointly required for in vivo growth and virulence
Mycobacterium tuberculosis isocitrate lyases 1 and 2 are jointly required for in vivo growth and virulence
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DOI：
10.1038/nm1252
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发表时间：
2005-06-01
期刊：
影响因子：
82.9
通讯作者：
McKinney, JD
中科院分区：
文献类型：
--
作者：
Muñoz-Elías, EJ;McKinney, JD
参与脂肪酸分解代谢的基因在分枝杆菌属中经历了广泛的重复，其中包括麻风病和结核病的病原。在这里，我们表明乙醛酸循环酶异柠檬酸裂解酶（ICL）的原核和真核样异构体是结核分枝杆菌脂肪酸分解代谢和毒力所必需的。尽管分别编码icl1和icl2的基因icl1或icl2的缺失对巨噬细胞和小鼠中的细菌生长几乎没有影响，但这两个基因的缺失导致细胞内复制完全受损，并迅速从肺部清除。利用一种双特异性ICL抑制剂，证明了以ICL1和ICL2为靶点进行化学抑制的可行性，该抑制剂可阻断结核分枝杆菌在脂肪酸和巨噬细胞中的生长。哺乳动物中ICL同源物的缺失将促进乙醛酸循环抑制剂作为治疗结核病的新药的开发。
Genes involved in fatty acid catabolism have undergone extensive duplication in the genus Mycobacterium, which includes the etiologic agents of leprosy and tuberculosis. Here, we show that prokaryotic- and eukaryotic-like isoforms of the glyoxylate cycle enzyme isocitrate lyase (ICL) are jointly required for fatty acid catabolism and virulence in Mycobacterium tuberculosis. Although deletion of icl1 or icl2, the genes that encode ICL1 and ICL2, respectively, had little effect on bacterial growth in macrophages and mice, deletion of both genes resulted in complete impairment of intracellular replication and rapid elimination from the lungs. The feasibility of targeting ICL1 and ICL2 for chemical inhibition was shown using a dual-specific ICL inhibitor, which blocked growth of M. tuberculosis on fatty acids and in macrophages. The absence of ICL orthologs in mammals should facilitate the development of glyoxylate cycle inhibitors as new drugs for the treatment of tuberculosis.