NOVEL DRUG DESIGN AND HIGH THROUGHPUT SCREENING

考虑到多重耐药菌株的增加，新型抗生素的开发刻不容缓 结核病、疟疾、艾滋病等疾病以及迄今为止未知的疾病的出现，例如 非典。传染病，特别是那些涉及耐药病原体的传染病，已经加剧 社会经济因素的影响，导致少数民族人口之间存在广泛的健康差距。我们的长 长期目标是发现和开发新型抗生素来对抗传染病（特别是那些 由耐药病原体引起），为消除健康差距做出贡献。作为一个 少数族裔机构研究基础设施 (RIMI) 计划支持申请的子项目，我们 提议通过互补和综合的新方法推进抗生素药物的发现 宿主防御、微生物基因组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疗法的潜力，在此基础上 这是我们最近支持脂质新颖的体内防御作用的实验数据的基础。在另一个 在前面，我们将利用增强的研究能力来识别其他新颖的化学结构 通过高通量筛选不同化合物库来发挥抗菌活性。预计一个 在稳定提供强效抗菌化合物的同时，我们将尝试开发一种新颖且更有效的抗菌化合物 通过以下方式识别这些有效抑制剂（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，是 这将为新发现和合理药物设计提供新的见解和策略。 优先抗菌靶点-抑制剂对。在内部和外部导师的指导和访问下 通过 RIMI 资助开发高通量筛选和化学/分子分析仪器 机制，研究人员将能够建立一个新颖的综合药物发现平台，该平台将 有助于对抗耐药病原体并努力消除不同人群之间的健康差距 少数民族人口。

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.