NOVEL DRUG DESIGN AND HIGH THROUGHPUT SCREENING

考虑到多重耐药菌株的增加，开发新型抗生素是当务之急 肺结核、疟疾、艾滋病等疾病，以及迄今未知的疾病， 非典传染病，特别是涉及耐药病原体的传染病， 由于社会经济因素的影响，导致少数民族人口之间普遍存在健康差距。我们漫长 长期目标是发现和开发新的抗生素来对抗传染病（特别是那些 由耐药病原体引起的疾病），有助于消除健康差距。作为 少数民族机构研究基础设施（RIMI）计划支持申请的子项目，我们 建议通过互补和综合的新方法来推进抗生素药物的发现， 宿主防御、微生物基因组学和基本分子识别观点。在 特别是，我们将评估天然宿主防御脂质作为抗菌治疗剂的潜力， 我们最近的实验数据支持脂质的新的体内防御作用的基础。在另一 在此之前，我们将利用增加的研究能力来确定其他新的化学结构， 通过高通量筛选不同的化合物文库来鉴定抗微生物活性。期待着一个 稳定提供有效的抗菌化合物，我们将尝试开发一种新的，更有效的 鉴定这些有效抑制剂（包括基于脂质的抑制剂）的细胞靶标的方法， 调节必需靶蛋白的表达。此外，我们将探索和评估分子 阳离子-π相互作用作为配体-蛋白质识别和结合的潜在新机制， 这将为那些新发现的药物设计提供新的见解和策略， 优先选择抗菌靶标-抑制剂对。在内部和外部导师的指导下， 通过RIMI资助的高通量筛选和化学/分子分析仪器 机制，研究人员将能够建立一个新的和综合的药物发现平台， * 有助于防治耐药病原体，并努力消除 少数族裔人口。

Development of novel antibiotics is of utmost urgency, considering the increase in multi-drug resistant strains in diseases like tuberculosis, malaria, AIDS, and the emergence of hitherto unknown diseases such as SARS. Infectious diseases, especially those that involve drug resistant pathogens, have been exacerbated by socioeconomic factors, resulting in widespread health disparities among minority populations. Our long term objective is to discover and develop novel antibiotics to combat infectious diseases (in particular those caused by drug resistant pathogens), contributing to the effort of elimination of health disparities. As a subproject of an application for Research Infrastructure in Minority Institutions (RIMI) Program support, we propose to advance antibiotic drug discovery through complementary and integrated novel approaches from the host defense, the microbial genomic, and the fundamental molecular recognition perspectives. In particular, we will assess the potential of natural host defense lipids as antimicrobial therapeutics, building on the foundation of our recent experimental data in support of lipids' novel in vivo defensive roles. On another front, we will leverage the increased research capacity to identify additional novel chemical structures with antimicrobial activities through high throughput screening of diverse compound libraries. Anticipating a steady provision of potent antibacterial compounds, we will attempt to develop a novel and more efficient method of identifying the cellular targets for these potent inhibitors (including lipid-based inhibitors) through modulated expression of essential target proteins. Furthermore, we will probe and evaluate the molecular cation-pi interaction as a potential novel mechanism of ligand-protein recognition and binding, the result of which would provide new insight and strategies for rational drug design for those newly discovered and prioritized antimicrobial target-inhibitor pairs. With guidance from internal and external mentors and access to high throughput screening and chemical/molecular analysis instrumentation through RIMI funding mechanism, the investigators will be able establish a novel and integrated drug discovery platform that will contribute to the fight against drug resistant pathogens and the effort to eliminate health disparities among minority populations.