Integrated Antimicrobial Drug Discovery Scheme for Multidrug Resistant Bacteria

描述（由申请人提供）：多重耐药细菌作为生物恐怖主义制剂的威胁，以及医院环境中病原体耐药性的增加，构成了严重的和潜在的破坏性医疗问题，需要使用新型抗生素的概念性新治疗方式。为了满足这一需求，我们提出了一个应用研究计划，旨在开发和实验验证一个综合的抗菌药物发现计划。特别是，由于代谢活性是所有原核生物功能的关键整合者，通过对其系统水平代谢组织的分析，我们将鉴定出那些细菌酶，其活性单独或组合在任何时候都是三种A类细菌生物恐怖剂和两种重要的病原菌在医院环境中具有显著的多药耐药性问题的可行性所需的。然后，我们将确定并实验验证一系列针对这些酶靶点的小分子抑制剂，这些抑制剂随后可以作为开发新抗生素的结构先导。拟议的项目将在一个完善的框架内进行，在分子生物学家和医生科学家的研究小组之间进行紧密整合的多学科努力，在细菌代谢网络的理论和实验分析方面具有经验（Z。N. Oltvai），一位理论物理学家，在评估复杂网络的结构和动力学特征方面有经验（A. L. Barabasi），一家在基因组注释、代谢重建和相应的湿实验室确认方面具有丰富经验的生物技术公司（Integrated Genomics，Inc.），以及在计算药物设计和开发方面具有丰富经验的有机和计算化学家（O。Wiest）。该项目将进一步得到四名顾问的积极计算和实验支持。

DESCRIPTION (provided by applicant): The threat of multi-drug resistant bacteria as bioterrorism agents, but also the increasing drug resistance of pathogens in a hospital setting, poses a serious and potentially devastating medical problem that requires conceptually new treatment modalities using novel antibiotics. To meet this need, we propose an applied research program that aims to develop and experimentally validate an integrated antimicrobial drug discovery scheme. In particular, as metabolic activity is a key integrator of all prokaryotic functions, through the analysis of their system-level metabolic organization we will identify those bacterial enzymes whose activity, alone or in combination, is required at all times for the viability of three Category A bacterial bioterrorism agents and two important pathogenic bacteria with significant problem of multidrug resistance in the hospital setting. We will then identify and experimentally validate a series of small-molecule inhibitors against these enzyme targets, which can subsequently serve as structural leads for the development of new antibiotics. The proposed project will be carried out in a framework of a well-established, tightly integrated multidisciplinary effort among research groups of a molecular biologist and physician-scientist with experience in the theoretical and experimental analysis of bacterial metabolic networks (Z. N. Oltvai), a theoretical physicist with experience in assessing the structural and dynamical features of complex networks (A.-L. Barabasi), a biotechnology company with extensive experience with genome annotation, metabolic reconstruction and corresponding wet lab confirmation (Integrated Genomics, Inc.), and an organic and computational chemist with extensive experience in computational drug design and development (O. Wiest). The project will be further aided by the active computational and experimental support of four Consultants.