Project Summary/Abstract This proposal describes our program focused on the development of novel chemical reactions for complex molecule synthesis, innovative strategies for molecule synthesis, and the application of these reactions and strategies to antimicrobial natural products The objective of the proposed research is to develop a scalable and expedient approach to several bioactive natural product families and leverage the synthetic work to develop new chemical probes and lead compounds for therapeutic development. We have developed several programs in this regard over our previous 5 years of NIH support and are excited to expand our efforts while advancing our existing projects to the next level. Of particular interest to date are polycyclic guanidine, oxazolidinone, curvulamines and absyssomicins to explore antimicrobial and/or anti-biofilm activity. We expect that our synthetic work will provide new reactions to construct molecules of broad utility and lead to approaches to natural products that enable their use as chemical probes. These synthetic studies are complimented by in-house chemical biology studies to explore the activity and mechanism of both natural products and analogs against clinically relevant diseases. Taken together, these efforts will provide a framework for the development of new synthetic chemistry and potential lead compounds for the treatment of bacterial infections as well as other diseases as new activity is uncovered.