Integrated Antimicrobial Drug Discovery Scheme for Multidrug Resistant Bacteria

描述(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日益增长的耐药性，构成了一个严重的、可能具有破坏性的医学问题，需要从概念上使用新的抗生素进行新的治疗方式。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综合抗菌药物发现方案。特别是，由于代谢活性是所有原核功能的关键整合因素，通过对其系统级代谢组织的分析，我们将确定那些单独或联合使用其活性是三种A类细菌生物恐怖分子和两种在医院环境中存在严重多药耐药性问题的重要病原菌生存所需的细菌酶。然后，我们将识别并实验验证一系列针对这些酶靶标的小分子抑制剂，这些靶标随后可以作为开发新抗生素的结构线索。拟议的项目将在一个成熟的、紧密集成的多学科工作框架内进行，研究小组包括一位在细菌代谢网络的理论和实验分析方面有经验的分子生物学家和内科科学家(Z.N.Oltwai)，一位在评估复杂网络的结构和动力学特征方面有经验的理论物理学家(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有丰富经验的生物技术公司(集成基因组公司)，以及一位在计算药物设计和开发方面有丰富经验的有机化学家和计算化学家(O.Wiest)。该项目将得到四位顾问在计算和实验方面的积极支持。

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.