Targeting NAD biosynthesis in Mycobacterium tuberculosis

 描述(申请人提供)：结核分枝杆菌(结核分枝杆菌)耐多药和广泛耐药菌株的出现是结核病(TB)的病原体，对结核病控制构成重大威胁。迫切需要开发针对以前未探索的细胞过程的新的、更有效的抗结核药物。这项提议的目标是寻找一类新的抗结核分枝杆菌活性的抗微生物化合物。烟酰胺单核苷酸腺苷转移酶(NADD)是NAD生物合成的关键酶，是抗细菌病原体药物开发的重要靶点。近年来，已经有许多NADD抑制剂被开发和验证，以对抗大肠杆菌、枯草芽孢杆菌和炭疽杆菌。已公布的数据表明，NADD是分枝杆菌生长和生存所必需的。因此，这一最新进展为将该酶作为开发新型抗结核药物的靶点提供了一个起点。本方案中的实验旨在使用结构生物学方法和我们最近开发的虚拟筛选(VS)方法相结合的方式来寻找Mtb NADD的抑制剂。我们建议使用我们的Mtb Nadd的晶体结构和先前发现的对大肠杆菌和炭疽杆菌Nadd具有活性的支架，应用迭代配体-基于结构的VS方法来发现NADD抑制剂。VS方法将利用数据库中已被证明对人类安全的经批准的药物。在这个项目成功完成后，我们将获得一些有效和安全的先导化合物，这些化合物将在体内研究中得到进一步验证。拟议研究中制定的策略也将适用于其他医学相关目标。

 DESCRIPTION (provided by applicant): Emergence of multidrug-resistant and extensively drug-resistant strains of Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), represents a major threat to TB control. There is an urgent need for development of new and more effective anti-tubercular drugs targeting previously unexplored cellular processes. The goal of this proposal is to find a novel class of antimicrobial compounds active against Mtb. Nicotinamide mononucleotide adenylyltransferase (NadD), an essential enzyme of NAD biosynthesis, represents a highly promising target for drug development against bacterial pathogens. In recent years there have been a number of NadD inhibitors developed and validated against Escherichia coli, Bacillus subtilis and B. anthracis. Published data indicate tha NadD is required for the growth and survival of mycobacteria. Thus, this recent progress provides a starting point for pursuing this enzyme as a target for the development of novel anti-tubercular drugs. The experiments in this proposal are designed to find inhibitors of Mtb NadD using a combination of structural biology approach and our recently developed virtual screening (VS) methodology. We propose to use our crystal structure of Mtb NadD and previously identified scaffolds active against E. coli and B. anthracis NadD, to apply an iterative ligand- an structure-based VS approach to discover the NadD inhibitors. The VS method will exploit databases with approved drugs that have already been shown to be safe in humans. Upon successful completion of this project we will obtain a number of potent and safe lead compounds that would be further validated in in vivo studies. The strategies developed in the proposed study will be also applicable to other medically relevant targets.