Targeting NAD biosynthesis in Mycobacterium tuberculosis

 描述（由申请方提供）：结核病（TB）的病原体结核分枝杆菌（Mtb）的多重耐药和广泛耐药菌株的出现是对TB控制的主要威胁。目前迫切需要开发新的和更有效的抗结核药物靶向以前未探索的细胞过程。该提案的目标是找到一类新的抗结核菌活性的抗微生物化合物。烟酰胺单核苷酸腺苷酰转移酶（NadD）是NAD生物合成的必需酶，是一个非常有前途的抗细菌病原体药物开发的目标。近年来，已经开发了许多针对大肠杆菌、枯草芽孢杆菌和B的NadD抑制剂并对其进行了验证。炭疽病已发表的数据表明NadD是分枝杆菌生长和存活所必需的。因此，这一最新进展提供了一个起点，追求这种酶作为新的抗结核药物的发展目标。在这个建议中的实验被设计为使用结构生物学方法和我们最近开发的虚拟筛选（VS）方法的组合来寻找Mtb NadD的抑制剂。我们建议使用我们的Mtb NadD晶体结构和先前鉴定的对E. coli和B. anthracis NadD，应用迭代配体-基于结构的VS方法来发现NadD抑制剂。VS方法将利用已被证明对人类安全的已批准药物的数据库。成功完成该项目后，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进一步验证。拟议研究中制定的策略也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.