Institute of Modern Biopharmaceuticals, State Key Laboratory Breeding Base of Eco-Enviroment and Bio-Resource of the Three Gorges Area, School of Life Sciences, Southwest University, Beibei, Chongqing 400715, China.
Int J Biol Sci. 2011 Apr 7;7(3):376-82. doi: 10.7150/ijbs.7.376.
Mycobacterium tuberculosis (MTB) remains one of the most significant human pathogens since its discovery in 1882. An estimated 1.5 million people died from tubercle bacillus (TB) in 2006, and globally, there were an estimated 9.27 million incident cases of TB in 2007. Glyoxylate bypass pathway occurs in a wide range of pathogens and plays a key role in the pathogenesis of Mycobacterium tuberculosis. Isocitrate lyase (ICL) can catalyses the first step of this pathway, and reversibly cleaves isocitrate into succinate and glyoxylate. So, ICL may represent a good drug target for the treatment of tuberculosis. ICL was cloned, expressed, and purified, and a high-throughput screen (HTS) developed to screen active molecule from a mannich base compounds library for inhibition of ICL. This assay had signal to noise (S/N) of 650.6990 and Z' factor of 0.8141, indicating that the assay was suitable for HTS. Screening of a collection of 124 mannich base compounds resulted in the identification of one mannich base compound, which has a significant inhibitory activity. So, a new family of compound was first reported to inhibit the activity of Mycobacterium tuberculosis ICL. This family of compound might offer new avenue to explore better anti-tuberculosis and fungi drugs.
结核分枝杆菌（MTB）自 1882 年被发现以来，一直是最重要的人类病原体之一。据估计，2006 年有 150 万人死于结核杆菌（TB），全球 2007 年估计有 927 万人新患结核病。乙醛酸旁路途径广泛存在于病原体中，在结核分枝杆菌的发病机制中起着关键作用。异柠檬酸裂合酶（ICL）可以催化该途径的第一步，可逆地将异柠檬酸裂解为琥珀酸和乙醛酸。因此，ICL 可能代表治疗结核病的一个很好的药物靶点。我们克隆、表达和纯化了 ICL，并开发了一种高通量筛选（HTS）方法，从曼尼希碱基化合物库中筛选出抑制 ICL 的活性分子。该测定的信号噪声比（S/N）为 650.6990，Z'因子为 0.8141，表明该测定适合 HTS。对 124 种曼尼希碱基化合物的筛选鉴定出一种曼尼希碱基化合物，对 ICL 具有显著的抑制活性。因此，首次报道了一类新的化合物可抑制结核分枝杆菌 ICL 的活性。这类化合物可能为探索更好的抗结核和抗真菌药物提供了新途径。
