New Methods and Chemical Tools Against Multi Drug-resistant Bacterial Infections ABSTRACT The central theme of our lab revolves around small molecules. We contribute to developing new methods and strategies to access small molecules of biological and medicinal relevance and using them as tools to probe biological questions or human diseases. This proposal outlines our ongoing efforts and future directions of two seemingly disparate programs that we envision merging into a ligand-discovery platform using 19F NMR. One of our research program's focus areas is on fluorinated alkenes with a fascinating chemical reactivity portfolio primarily due to the polarity inversion feature. We are investigating the polarity inversion property of fluorinated alkenes, which we recognize will solve the long-standing problem of regioselectivity in fluorinated heterocyclic compounds. Our work demonstrated the applicability of FAs in generating regioselective access to nitrogen- containing fluorinated heterocycles. The other research area is focused on seeking new chemical tools and innovative strategies to address the evolution of antibiotic-resistance strains that have impeded antibiotic treatment and rendered them ineffective, costing heavily on the healthcare industry. We are currently probing the MraY enzyme, a key component of cell wall synthesis, using conventional structure-based rational design strategy and unconventional discovery platforms of targeted protein degradation and 19F NMR-based ligand screening. An R35 MIRA award would help accomplish our goals and enable the merger of our two research themes. Successful completion of these studies will allow us to contribute broadly in gaining insights into the function, structure, and mechanism of inhibition of antibacterial targets using fluorinated probes, small-molecule degraders, and a 19F NMR-based screening platform. These studies will lead to antibacterials with new chemical entities with novel mechanism of action that are urgently needed to replenish our arsenal of new and existing antibiotics. An R35 MIRA award would also foster our existing and new collaborations within the university, across the United States, and internationally. This research program will help the participating graduate, and undergraduate students and postdoctoral scholars enhance and learn new skills in interdisciplinary sciences while working in a highly collaborative and multidisciplinary environment.