Increased human exposure to pathogens couples with rising antibiotic resistance and slow antibiotic development to pose a nearly insurmountable human health challenge. My group’s work aims to discover proteins critical for pathogen survival, to reveal important insights into their mechanisms of action, and to develop chemical tools that precisely modulate their functions. By focusing on pathogens with limited or unique metabolic capabilities, we aim to reveal novel biomarkers and antibiotic targets that are less likely to evade inhibitors. This talk will describe our multipronged approach that employs metabolomics, protein biochemistry, biophysics, and data science to accelerate the proteome-wide discovery of critical metabolite handling proteins in human pathogens. Furthermore, ongoing efforts to identify effective narrow-spectrum anti-infectives will be described.