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

• Published in: PLoS genetics Vol. 12; no. 6; p. e1006124
• Main Authors: Shiver, Anthony L, Osadnik, Hendrik, Kritikos, George, Li, Bo, Krogan, Nevan, Typas, Athanasios, Gross, Carol A
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 29-06-2016; Public Library of Science (PLoS)
• Subjects: 60 APPLIED LIFE SCIENCES; Aminoglycosides - pharmacology; Anti-Bacterial Agents - pharmacology; Antibiotics; BASIC BIOLOGICAL SCIENCES; Biology and Life Sciences; Complications and side effects; Crop diseases; Crops, Agricultural - drug effects; Datasets; Disease susceptibility; Drug resistance; Drug Resistance, Microbial - genetics; E coli; Escherichia coli; Escherichia coli K12 - genetics; Funding; Genes; Genetic aspects; Genetic testing; Genomics; Genomics - methods; Health aspects; Medicine and Health Sciences; Methods; Microbial drug resistance; Mutation; Nucleosides - pharmacology; Peptides; Plant Diseases - microbiology; Plants - microbiology; Research and Analysis Methods; Software; Studies
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1006124

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.