Integrated genomics and chemical biology herald an era of sophisticated antibacterial discovery, from defining essential genes to target elucidation

The golden age of antibiotic discovery in the 1940s–1960s saw the development and deployment of many different classes of antibiotics, revolutionizing the field of medicine. Since that time, our ability to discover antibiotics of novel structural classes or mechanisms has not kept pace with the ever-growing threat of antibiotic resistance. Recently, advances at the intersection of genomics and chemical biology have enabled efforts to better define the vulnerabilities of essential gene targets, to develop sophisticated whole-cell chemical screening methods that reveal target biology early, and to elucidate small molecule targets and modes of action more effectively. These new technologies have the potential to expand the chemical diversity of antibiotic candidates, as well as the breadth of targets. We illustrate how the latest tools of genomics and chemical biology are being integrated to better understand pathogen vulnerabilities and antibiotic mechanisms in order to inform a new era of antibiotic discovery.