Development of Aspartate Pathway Inhibitors as Novel Antibiotics

描述(申请人提供)：我们正面临来自感染性生物的日益增长的威胁，这些生物甚至对最新开发的抗生素产生抗药性，这些抗生素针对细胞壁组装和蛋白质生物合成的关键步骤。为了应对这一威胁，我们需要对抗菌素开发采取更广泛的方法，以确定具有不同作用模式的新靶点，从而导致新的药物类别。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择的关键酶，这些酶可能成为新的药物靶点。这项研究提案的目的是利用我们对关键微生物阿斯巴甜途径中的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，这些感染性生物的阿斯巴甜2-半醛脱氢反应是新药物干预的有吸引力和未经测试的靶标，这一核心酶的选择性抑制剂将导致新型抗菌剂的开发，这些新药将高效地对抗来自多药耐药感染性微生物日益增长的威胁。这一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)结合新的抑制剂片段以产生有效和选择性的抑制剂；以及3)从选定的病原体中开发针对ASA脱氢的特定种类的抑制剂。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，产生在微生物发展的广泛关键阶段发挥作用的各种基本产品。用有效和选择性的抑制剂在早期阶段关闭这些途径将会引起无数的问题，如果有机体想要生存下来，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。作为拟议研究的结果，我们希望确定几个有效的先导化合物，以高亲和力和提高选择性来靶向阿斯巴甜途径的这一关键代谢酶。开发对特定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。这项拟议的研究具有重要意义，因为这些特定目标的实现将有助于验证抗生素靶向的扩展范例，并鼓励更广泛的药物开发视角。 与公共卫生相关：微生物对人类健康的威胁正在增加，这是因为已进化成对许多可用的临床抗生素产生抗药性的感染性有机体的数量急剧增加。因此，可用于治疗这些感染的有效抗生素的数量不断减少，以及具有新作用机制的候选药物的缺乏，使得寻找针对新的微生物靶点的新抗生素变得更加紧迫。

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.