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.

1940 年代至 60 年代是抗生素发现的黄金时代，见证了许多不同类别抗生素的开发和部署，彻底改变了医学领域。从那时起，我们发现新结构类别或机制的抗生素的能力跟不上抗生素耐药性日益增长的威胁。最近，基因组学和化学生物学交叉领域的进展使得人们能够更好地定义基本基因靶标的脆弱性，开发能够及早揭示靶标生物学的复杂全细胞化学筛选方法，并阐明小分子靶标和作用模式。有效地。这些新技术有可能扩大候选抗生素的化学多样性以及目标的广度。