Menaquinone biosynthesis:a drug target in Gram-positive bacteria

描述（由申请人提供）：甲基萘醌合成（特别是MenA）的有效抑制剂。已经鉴定了结核分枝杆菌，它们也是分枝杆菌生长的有效抑制剂。由于甲基萘醌的利用是革兰氏阳性生物体的特征，因此这些化合物也对诸如耐甲氧西林金黄色葡萄球菌和表皮葡萄球菌的生物体具有活性，并且预期也对炭疽杆菌和单核细胞增生李斯特菌有效。在此被鉴定为MenA抑制剂的化合物首先被开发为胆固醇合成抑制剂，并且因此已知在哺乳动物中是生物可利用的并且具有低内在毒性。这些化合物将通过合成药物化学循环进行“逆向设计”，然后对化合物进行甲萘醌和细菌生长抑制剂的评价。这些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。此外，将确定MenA的催化机制和参与甲基萘醌合成的替代药物靶标。本申请的具体目的是：1）测试假设参与甲基萘醌合成的MenA、GrcC1、GrcC2和Rv 0558基因。结核病，本质上。2)设计、合成和测试一类新的抗结核药物，其衍生自氧化角鲨烯环化酶抑制剂。3)定义MenA催化的机制，表征GrcC1和Rv0558的酶特性，并为那些被证明是必不可少的酶开发高通量筛选相容性测定。该研究计划的结果预计将在发现新的先导化合物方面具有重要意义，这些化合物可以开发成新药，以对抗革兰氏阳性NIAID A类，B和C类优先病原体，以及革兰氏阳性细菌引起的新兴疾病。

DESCRIPTION (provided by applicant): 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 application are to: 1) test MenA, GrcC1, GrcC2 and Rv0558 genes hypothesized to participate in menaquinone synthesis in M. tuberculosis, for essentiality. 2) Design, synthesize and test a new class of anti-tuberculosis agents derived from an oxidosqualene cyclase inhibitor. 3) Define the mechanism of MenA catalysis, characterize the enzymatic properties of GrcC1 and Rv0558 and develop high-throughput screening compatible assays for those enzymes shown to be essential. The results of this research program 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.