Evolution shapes metabolic function and niche-specific antimicrobial targets in pathobionts

Treatment of infections with traditional antimicrobials has become difficult due to the growing antimicrobial resistance crisis, necessitating the development of innovative approaches for deeply understanding pathogen function. Here, we generated a collection of genome-scale metabolic network reconstructions to gain insight into evolutionary drivers of metabolic function. We determined physiological location is a major driver of evolution of metabolic function. We observed that stomach-associated pathobionts had the most unique metabolic phenotypes and identified three essential genes unique to stomach pathobionts across diverse phylogenetic relationships. We demonstrate that inhibition of one such gene, thyX , inhibited growth of stomach- specific pathobionts exclusively, indicating possible physiological niche-specific targeting. This pioneering approach is the first step to using unique metabolic signatures to inform targeted antimicrobial therapies. One sentence summary A data-driven approach to drug target discovery through metabolic signatures of diverse pathogens conserved across body-sites.