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.