Shiver Anthony L, Osadnik Hendrik, Kritikos George, Li Bo, Krogan Nevan, Typas Athanasios, Gross Carol A
Graduate Group in Biophysics, University of California, San Francisco, San Francisco, California, United States of America.
Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, California, United States of America.
PLoS Genet. 2016 Jun 29;12(6):e1006124. doi: 10.1371/journal.pgen.1006124. eCollection 2016 Jun.
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要更深入地了解决定细菌对抗生素敏感性的遗传因素。在此，我们描述了一项在大肠杆菌K-12中进行的化学基因组筛选，该筛选旨在通过聚焦于一组26种抗生素以及其他作用方式和耐药决定因素特征不明的应激因素，来发现抗生素耐药性的新方面。我们表明，该筛选鉴定出了这些抗生素的新耐药决定因素，包括用于治疗稻瘟病和火疫病等作物疾病的两种抗菌药物春日霉素和杀稻瘟菌素的共同特征。遵循这一特征，我们使用遗传和生化方法进一步研究了大肠杆菌对春日霉素和杀稻瘟菌素敏感的机制基础。我们提供的证据表明，这些化合物劫持了一组重叠的肽ABC转运体以进入细菌细胞。摄取的丧失可能是细菌植物病原体中春日霉素耐药性发展的一种未被充分认识的机制。
