Development of Aspartate Pathway Inhibitors as Novel Antibiotics

开发天冬氨酸途径抑制剂作为新型抗生素

• 批准号: 8450269
• 负责人: RONALD Edward VIOLA
• 金额: $ 33.85万
• 依托单位: UNIVERSITY OF TOLEDO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-15 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8450269
• 关键词: Achievement; Advanced Development; Affinity; Anabolism; Antibiotics; Area; Aspartame; Aspartate; Aspartate-Semialdehyde Dehydrogenase; Binding; Cell Wall; Chemistry; Clinical; Collaborations; Complex; Coupled; Coupling; Crystallization; Crystallography; DNA biosynthesis; Defense Mechanisms; Development; Drug Design; Drug Targeting; Drug resistance; Environment; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Enzymes; Evaluation; Family; Generations; Goals; Health; Human; Individual; Infection; Infectious Agent; Intervention; Investigation; Knowledge; Laboratories; Lead; Length; Life Cycle Stages; Metabolic; Microbe; Modification; Multi-Drug Resistance; Organism; Outcome; Oxidoreductase; Pathway interactions; Pharmaceutical Preparations; Pharmacy facility; Phase; Physiological; Population; Property; Protein Biosynthesis; Proteins; Research; Research Infrastructure; Research Proposals; Resistance; Resources; Route; Series; Source; Specificity; Staging; Structural Models; Structure; Testing; Toxic effect; Universities; Work; X ray diffraction analysis; X-Ray Diffraction; antimicrobial; base; college; combat; design; drug candidate; drug development; flexibility; improved; inhibitor/antagonist; innovation; meetings; microbial; microorganism; novel; programs; public health relevance; response; screening; weapons; working group

DESCRIPTION (provided by applicant): We are facing a growing threat from infectious organisms that are becoming resistant to even the most recently developed antibiotics that target essential steps in cell wall assembly and protein biosynthesis. To combat this threat we need a broader approach to antimicrobial development that identifies novel targets with different modes of action, thereby leading to new classes of drugs. Our long term goal of this research program is to identify and examine key enzymes selected from essential microbial pathways that can potentially serve as novel drug targets. The objective for this research proposal is to use our extensive knowledge of the core enzymes in the essential microbial aspartame pathway as a guide for the development of effective lead compounds. It is our hypothesis that the aspartame 2-semialdehyde dehydrogenises of these infectious organisms are attractive and untested targets for novel drug intervention, and that selective inhibitors of this core enzyme will lead to the development of new classes of antimicrobials that will be highly effective against the growing threat from multidrug resistant infectious organisms. This hypothesis will be testing by the following specific aims: 1) modify the initial ASA dehydrogenate inhibitors to develop advanced lead compounds; 2) combine new inhibitor fragments to produce potent and selective inhibitors; and 3) develop species-specific inhibitors against ASA dehydrogenises from selected pathogenic organisms. The innovation of our proposed work is the exploration of new paradigms for antibiotic development. Our plan is to select unique microbial pathways which produce a variety of essential products that function in a wide range of critical phases of microbial development. Shutting down these pathways in their early stage with potent and selective inhibitors will cause a myriad of problems that the organism must try to overcome if it is to survive. A second innovative aspect of our approach challenges the existing paradigm of exclusively targeting the development of broad spectrum antibiotics. As an outcome of the proposed studies we expect to identify several validated lead compounds that target this key metabolic enzyme of the aspartame pathway with high affinity and improved selectivity. Developing advanced lead compounds with specificity against selected pathogenic organisms will provide added value to these drug candidates. This proposed research is significant because achievement of these specific aims will help to validate an expanded paradigm for antibiotic targeting and encourage a broader view of drug development.

描述（由申请人提供）：我们面临着来自传染性生物体的日益严重的威胁，这些生物体甚至对最近开发的针对细胞壁组装和蛋白质生物合成中的关键步骤的抗生素产生了抗药性。为了应对这一威胁，我们需要更广泛的抗菌药物开发方法，确定具有不同作用模式的新靶标，从而开发出新类别的药物。我们该研究计划的长期目标是识别和检查从重要微生物途径中选择的关键酶，这些酶有可能作为新的药物靶点。该研究计划的目的是利用我们对基本微生物阿斯巴甜途径中核心酶的广泛知识作为开发有效先导化合物的指南。我们的假设是，这些传染性生物体的阿斯巴甜2-半醛脱氢是新颖药物干预的有吸引力且未经测试的靶点，并且这种核心酶的选择性抑制剂将导致新型抗菌药物的开发，这些抗菌药物将非常有效地对抗多重耐药感染性生物体日益增长的威胁。该假设将通过以下具体目标进行检验：1）修改最初的 ASA 脱氢抑制剂以开发先进的先导化合物； 2) 组合新的抑制剂片段以产生强效且选择性的抑制剂； 3) 开发针对选定病原生物的 ASA 脱氢作用的物种特异性抑制剂。我们提出的工作的创新之处在于探索抗生素开发的新范式。我们的计划是选择独特的微生物途径，生产出在微生物发育的广泛关键阶段发挥作用的各种重要产品。在早期阶段用有效的选择性抑制剂关闭这些途径将导致无数问题，生物体要想生存就必须设法克服这些问题。我们方法的第二个创新方面挑战了专门针对广谱抗生素开发的现有范式。作为拟议研究的结果，我们期望鉴定出几种经过验证的先导化合物，这些化合物以高亲和力和改进的选择性针对阿斯巴甜途径的这种关键代谢酶。开发对选定的病原生物具有特异性的先进先导化合物将为这些候选药物提供附加值。这项拟议的研究意义重大，因为这些具体目标的实现将有助于验证抗生素靶向的扩展范式，并鼓励更广泛的药物开发视野。