Development of Aspartate Pathway Inhibitors as Novel Antibiotics

描述（由申请人提供）：我们正面临着来自传染性生物体日益增长的威胁，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基本步骤的抗生素产生耐药性。为了应对这一威胁，我们需要更广泛的抗微生物药物开发方法，确定具有不同作用模式的新靶点，从而开发出新的药物类别。我们这项研究计划的长期目标是鉴定和检查从基本微生物途径中选择的关键酶，这些酶可能作为新的药物靶点。这项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导。我们的假设是，这些感染性生物的阿斯巴甜2-半醛脱氢是有吸引力的、未经测试的新型药物干预靶点，这种核心酶的选择性抑制剂将导致新型抗菌剂的开发，这些抗菌剂将对多药耐药感染性生物日益增长的威胁非常有效。这一假设将通过以下具体目标进行测试：1)修改初始的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产生强效和选择性抑制剂；3)从选定的致病生物中开发针对ASA脱氢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，产生各种基本产品，在微生物发育的广泛关键阶段发挥作用。在这些途径的早期阶段，用强效和选择性抑制剂关闭这些途径，将导致生物体必须努力克服的无数问题，如果它要生存下去。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例。作为拟议研究的结果，我们希望鉴定出几种经过验证的先导化合物，它们以高亲和力和高选择性靶向阿斯巴甜途径的关键代谢酶。开发针对特定致病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价值。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例，并鼓励更广泛的药物开发观点。

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.