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: 7887641
• 负责人: RONALD Edward VIOLA
• 金额: $ 36.01万
• 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/7887641
• 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 Delivery Systems; Drug Design; 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; Public Health; Research; Research Infrastructure; Research Proposals; Resistance; Resources; Route; Screening procedure; 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; 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. PUBLIC HEALTH RELEVANCE: The microbial threat to human health is growing due to the dramatic increase in the number of infectious organisms that have evolved to become resistant to many of the available clinical antibiotics. As a consequence, the decreasing number of effective antibiotics available to treat these infections and the dearth of drug candidates with novel mechanisms of action has lent a greater urgency to the search for new antibiotics against novel microbial targets.

描述（由申请人提供）：我们正面临着来自感染性生物体的日益增长的威胁，这些生物体甚至对最近开发的靶向细胞壁组装和蛋白质生物合成中的关键步骤的抗生素也产生了耐药性。为了应对这一威胁，我们需要一种更广泛的方法来开发抗菌药物，以确定具有不同作用模式的新靶标，从而产生新的药物类别。我们这项研究计划的长期目标是识别和检查从基本微生物途径中选出的关键酶，这些酶可能成为新型药物靶点。这项研究计划的目的是利用我们对微生物基本代谢途径中核心酶的广泛了解，作为开发有效先导化合物的指导。我们的假设是，这些感染性生物体的β-内酰胺2-半醛酶是新型药物干预的有吸引力且未经测试的靶标，并且该核心酶的选择性抑制剂将导致开发新类别的抗菌剂，其将高度有效地对抗来自多药耐药感染性生物体的日益增长的威胁。该假设将通过以下具体目标进行检验：1）修改初始阿萨代谢物抑制剂以开发高级先导化合物; 2）联合收割机新抑制剂片段以产生有效和选择性抑制剂; 3）开发针对来自选定病原体的阿萨代谢物的物种特异性抑制剂。我们所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，产生各种必需的产品，在微生物发展的广泛的关键阶段发挥作用。在早期阶段用有效和选择性的抑制剂关闭这些途径将导致无数的问题，如果生物体要生存，就必须努力克服这些问题。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。作为所提出的研究的结果，我们期望鉴定出几种经验证的先导化合物，其以高亲和力和改进的选择性靶向于甜菜碱途径的这种关键代谢酶。开发对选定的病原体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，因为实现这些特定目标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。 公共卫生相关性：微生物对人类健康的威胁正在增长，这是由于感染性生物体的数量急剧增加，这些生物体已经进化成对许多可用的临床抗生素具有抗性。因此，可用于治疗这些感染的有效抗生素数量的减少以及具有新作用机制的候选药物的缺乏使得寻找针对新微生物靶标的新抗生素变得更加紧迫。