Data from: 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.

对抗抗生素耐药性亟需深入解析决定细菌抗生素敏感性的遗传因子。本研究报道了一项在大肠杆菌K-12（Escherichia coli K-12）中开展的化学基因组筛选（chemical-genomic screen）：该筛选聚焦26种抗生素及其他作用模式与耐药决定因子均未被充分阐明的胁迫因素，旨在发掘抗生素耐药性的全新维度。研究证实，本次筛选可识别出上述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——春日霉素（kasugamycin）与杀稻瘟菌素S（blasticidin S）共有的特征标记。基于该特征标记，我们进一步通过遗传学与生物化学手段，解析了大肠杆菌对春日霉素与杀稻瘟菌素S的敏感性机制。本研究提供的证据表明，此类化合物通过劫持一组重叠的肽类ABC转运体（peptide ABC-importers）以进入细菌细胞。细菌植物病原菌对春日霉素产生耐药性的潜在机制或许正是摄取途径的缺失，而这一机制此前未受到足够重视。