Natural and engineered precision antibiotics in the context of resistance

Antibiotics are essential weapons in our fight against infectious disease, yet the consequences of broad-spectrum antibiotic use on microbiome stability and pathogen resistance are prompting investigations into more selective alternatives. Echoing the advent of precision medicine in oncology, precision antibiotics with focused activities are emerging as a means of addressing infections without damaging microbiomes or incentivizing resistance. Historically, antibiotic design principles have been gleaned from Nature, and reinvestigation of overlooked antibacterials is now providing scaffolds and targets for the design of pathogen-specific drugs. In this perspective, we summarize the biosynthetic and antibacterial mechanisms used to access these activities, and discuss how such strategies may be co-opted through engineering approaches to afford precision antibiotics.