A Chemical-Genomic Screen of Neglected Antibiotics Reveals Illicit Transport of Kasugamycin and Blasticidin S

Fighting antibiotic resistance requires a deeper understanding of the genetic factors that determine the antibiotic susceptibility of bacteria. Here we describe a chemical-genomic screen in Escherichia coli K-12 that was designed to discover new aspects of antibiotic resistance by focusing on a set of 26 antibiotics and other stresses with poorly characterized mode-of-action and determinants of resistance. We show that the screen identifies new resistance determinants for these antibiotics including a common signature from two antimicrobials, kasugamycin and blasticidin S, used to treat crop diseases like rice blast and fire blight. Following this signature, we further investigated the mechanistic basis for susceptibility to kasugamycin and blasticidin S in E. coli using both genetic and biochemical approaches. We provide evidence that these compounds hijack an overlapping set of peptide ABC-importers to enter the bacterial cell. Loss of uptake may be an underappreciated mechanism for the development of kasugamycin resistance in bacterial plant pathogens.

对抗抗生素耐药性，需深入解析决定细菌抗生素敏感性的遗传因素。本研究以大肠杆菌K-12（Escherichia coli K-12）为模型，开展了一项化学基因组筛选实验，通过聚焦26种抗生素及其他作用机制与耐药决定因子均未得到充分阐明的胁迫因素，以期发掘抗生素耐药性的全新层面。研究结果显示，该筛选可识别出这些抗生素的新型耐药决定因子，其中包含两类用于防治稻瘟病、火疫病等作物病害的抗菌剂——春雷霉素（kasugamycin）与杀稻瘟菌素S（blasticidin S）共有的特征信号。基于这一特征信号，我们进一步通过遗传学与生物化学方法，解析了大肠杆菌对春雷霉素及杀稻瘟菌素S的敏感性机制。本研究证实，这类化合物会通过一套重叠的肽类ABC转运蛋白（peptide ABC-importers）侵入细菌细胞；而摄取通路的缺失，可能是植物病原细菌产生春雷霉素耐药性的一种未被充分认知的机制。