title: A Chemical-Genomic Screen of Neglected Antibiotics Reveals Illicit Transport of Kasugamycin and Blasticidin S.
abstract: 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.
authors.affiliation: Graduate Group in Biophysics, University of California, San Francisco, San Francisco, California, United States of America.
authors.forename: Anthony L
authors.initials: AL
authors.lastname: Shiver
authors.affiliation: Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, California, United States of America.
authors.forename: Hendrik
authors.identifier: 0000-0002-1624-1322
authors.initials: H
authors.lastname: Osadnik
authors.affiliation: European Molecular Biology Laboratory, Genome Biology Unit, Heidelberg, Germany.
authors.forename: George
authors.initials: G
authors.lastname: Kritikos
authors.affiliation: Department of Chemistry, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Bo
authors.initials: B
authors.lastname: Li
authors.affiliation: QB3, California Institute for Quantitative Biosciences, San Francisco, California, United States of America.|Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, California, United States of America.|Gladstone Institutes, San Francisco, California, United States of America.
authors.forename: Nevan
authors.initials: N
authors.lastname: Krogan
authors.affiliation: European Molecular Biology Laboratory, Genome Biology Unit, Heidelberg, Germany.
authors.forename: Athanasios
authors.initials: A
authors.lastname: Typas
authors.affiliation: Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, California, United States of America.|QB3, California Institute for Quantitative Biosciences, San Francisco, California, United States of America.|Department of Cell and Tissue Biology, University of California, San Francisco, California, United States of America.
authors.forename: Carol A
authors.identifier: 0000-0002-5595-9732
authors.initials: CA
authors.lastname: Gross
mesh_terms: D000617:Aminoglycosides / Q000494:pharmacology*; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D018556:Crops, Agricultural / Q000187:drug effects; D004352:Drug Resistance, Microbial / Q000235:genetics*; D048168:Escherichia coli K12 / Q000235:genetics*; D023281:Genomics / Q000379:methods; D009705:Nucleosides / Q000494:pharmacology; D010935:Plant Diseases / Q000382:microbiology; D010944:Plants / Q000382:microbiology
chemical_list: D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D009705:Nucleosides; C004500:blasticidin S; C100305:kasugamycin