Systematic prediction, validation, prioritization and on-target lead discovery for next-generation antimicrobials

Antimicrobial resistance constitutes one of the biggest global challenges facing modern medicine. Yet antimicrobial discovery is impeded by the limited number of validated microbial targets, and the rapid development of resistance by pathogens to existing frontline therapeutics. Chemically sensitive amino acids on proteins are targets for covalent-mechanism drugs. These are potential Achilles' heels of pathogens, yet are underexploited as antimicrobial targets. Chemoproteomic approaches identify chemically sensitive residues via their intrinsic reactivity towards probe molecules, but do not integrate functional prioritization. This results in most of these chemically tractable protein targets being overlooked. A new cross-disciplinary functional chemoprotegenomics platform enables unbiased discovery and validation of chemically sensitive residues on proteins. This project will integrate emerging computational and experimental technologies from our labs to establish a high-throughput approach for discovering, validating, and selectively targeting chemically tractable residues in any pathogen, presenting a new paradigm for on-target antimicrobial drug discovery.