Analysis of metabolic pathways in mycobacteria to aid drug-target identification-猫眼课题宝

DOI：

10.1101/535856

发表时间：

2019-01

期刊：

bioRxiv

影响因子：

通讯作者：

中科院分区：

其他

文献类型：

作者：

Bridget P. Bannerman;S. Vedithi;J. Júlvez;P. Torres;V. Waman;A. Munir;Vítor Mendes;S. Malhotra;Marcin J. Skwark;S. Oliver;T. Blundell

三种相关的分枝杆菌是人类广泛感染的原因，面对日益增长的抗菌素耐药性，它们是密集研究和药物发现工作的重点。据世卫组织统计，结核病的病原体结核分枝杆菌目前是世界十大死亡原因之一；脓肿分枝杆菌，一组非结核分枝杆菌引起肺部感染和其他人类机会性感染；麻风分枝杆菌是麻风的病原体，在热带国家仍然流行。由于对标准抗菌药物的耐药性增加，迫切需要设计替代常规治疗策略。在这项研究中，我们提出了阻塞点和必要性数据集的比较分析，这将为新治疗方案的发展提供见解。我们阐明了这三种生物之间共享的关键代谢途径，并确定了具有广泛代谢影响的药物靶点，这些靶点对这三种生物是共同的。我们证明72%的阻塞点酶是结核分枝杆菌必需的蛋白质。我们还发现，78%的药物靶点存在于结核分枝杆菌、麻风分枝杆菌和脓肿分枝杆菌共有的代谢网络的多个途径中，包括氨基酸、碳水化合物、细胞结构、脂肪酸和脂质生物合成。在结核分枝杆菌和脓肿分枝杆菌之间共有的优先途径中发现了另外17%。我们对使用我们的分析确定的潜在药物靶点进行了比较结构建模，以评估药物可药性，并证明瓶颈分析在药物靶点鉴定方面的重要性。设计抗分枝杆菌新药的计算机模拟研究

Three related mycobacteria are the cause of widespread infections in man and are the focus of intense research and drug-discovery efforts in the face of growing antimicrobial resistance. Mycobacterium tuberculosis, the causative agent of tuberculosis, is currently one of the top ten causes of death in the world according to WHO; M. abscessus, a group of non-tuberculous mycobacteria causes lung infections and other opportunistic infections in humans; and M. leprae, the causative agent of leprosy, remains endemic in tropical countries. There is an urgent need to design alternatives to conventional treatment strategies, due to the increase in resistance to standard antibacterials. In this study, we present a comparative analysis of chokepoint and essentiality datasets that will provide insight into the development of new treatment regimes. We illustrate the key metabolic pathways shared between these three organisms and identify drug targets with a wide metabolic impact that are common to the three species. We demonstrate that 72% of the chokepoint enzymes are proteins essential to Mycobacterium tuberculosis. We show also that 78% of the drug targets, prioritized based on their presence in multiple paths on the metabolic network, are present in pathways shared by M. tuberculosis, M. leprae and M. abscessus, including biosynthesis of amino acids, carbohydrates, cell structures, fatty acid and lipid biosynthesis. A further 17% is found in the prioritised pathways shared between M. tuberculosis and M. abscessus. We have performed comparative structure modelling of potential drug targets identified using our analysis in order to assess druggability and demonstrate the importance of chokepoint analysis in terms of drug target identification. AUTHOR SUMMARY Computer simulation studies to design new drugs against mycobacteria

Analysis of metabolic pathways in mycobacteria to aid drug-target identification

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