Menaquinone biosynthesis: a drug target in Gram-positive bacteria

项目摘要： 甲基萘醌合成（特别是MenA）的有效抑制剂。结核病已经被发现， 也是分枝杆菌生长的有效抑制剂。由于甲基萘醌的使用是一个特点， 革兰氏阳性微生物，这些化合物也对微生物如甲氧西林耐药 金黄色葡萄球菌和表皮葡萄球菌，并预期对芽孢杆菌有效 炭疽菌和单核细胞增生李斯特菌。在这里被鉴定为MenA抑制剂的化合物，首先是 作为胆固醇合成抑制剂开发，因此已知在哺乳动物中是生物可利用的， 具有低的内在毒性。这些化合物将通过合成药物的循环进行“逆向设计”， 化学，然后评价化合物如甲基萘醌和细菌生长抑制剂。的 化合物也将被反选择以降低它们作为胆固醇合成抑制剂的有效性。在 此外，还介绍了MenA的催化机制和Menaquinone的替代药物靶点 合成将被识别。本提案的具体目标是：1）设计、合成和测试一种新的 衍生自氧化角鲨烯环化酶抑制剂的一类抗结核药。2)测试MenA，GrcC1， GrcC2、Rv0558和Rv3853是推测参与甲基萘醌合成的基因。 结核病，本质上。3)明确MenA催化的机理，表征酶促反应， GrcC1、GrcC2、Rv0558和Rv3853的特性，并开发高通量筛选兼容的 对这些酶的测定显示是必需的。 相关性： 这些结果有望在发现新的先导化合物方面具有重要意义， 开发成新的药物，以打击革兰氏阳性NIAID A类，B和C类优先病原体，以及 如革兰氏阳性菌引起的新兴疾病。

Project Summary: Potent inhibitors of menaquinone synthesis (specifically MenA) in M. tuberculosis have been identified, which are also effective inhibitors of mycobacterial growth. Since utilization of menaquinone is a characteristic of Gram-positive organisms, these compounds are also active against organisms such as methicillin resistant Stapylococcus aureus and Staphylococcus epidermidis, and are expected to be effective against Bacillus anthracis and Listeria monocytogenes as well. The compounds identified as MenA inhibitors here, were first developed as cholesterol synthesis inhibitors and, as such, are known to be bioavailable in mammals and to have low intrinsic toxicity. These compounds will be "retro-designed" via cycle of synthetic medicinal chemistry followed by evaluation of compounds as menaquinone, and bacterial growth inhibitors. The compounds will also be counter-selected to reduce their effectiveness as cholesterol synthesis inhibitors. In addition, the mechanism of catalysis of MenA and alternative drug targets involved in menaquinone synthesis will be identified. The Specific Aims of this proposal are to: 1) Design, synthesize and test a new class of anti-tuberculosis agents derived from an oxidosqualene cyclase inhibitor. 2) test MenA, GrcC1, GrcC2, Rv0558 and Rv3853, genes hypothesized to participate in menaquinone synthesis in M. tuberculosis, for essentiality. 3) Define the mechanism of MenA catalysis, characterize the enzymatic properties of GrcC1, GrcC2, Rv0558 and Rv3853 and develop high-throughput screening compatible assays for those enzymes shown to be essential. Relevance: The results are expected to be of significance in terms of discovering new lead compounds that can be developed into new drugs to combat Gram-positive NIAID category A, B and C priority pathogens, as well as, emerging diseases caused by Gram-positive bacteria.