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

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  • Shiver, Anthony L.
    • Other Affiliation: Graduate Group in Biophysics; University of California; San Francisco
  • Osadnik, Hendrik
    • ORCID: 0000-0002-1624-1322
    • Other Affiliation: Department of Microbiology and Immunology; University of California; San Francisco
  • Kritikos, George
    • Other Affiliation: European Molecular Biology Laboratory; Genome Biology Unit
  • Li, Bo
    • Affiliation: College of Arts and Sciences, Department of Chemistry
  • Krogan, Nevan
    • Other Affiliation: Department of Cellular and Molecular Pharmacology; University of California; San Francisco
  • Typas, Athanasios
    • Other Affiliation: European Molecular Biology Laboratory; Genome Biology Unit
  • Gross, Carol A.
    • Other Affiliation: QB3; California Institute for Quantitative Biosciences
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.
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  • Article
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  • In Copyright
Journal title
  • PLoS Genetics
Journal volume
  • 12
Journal issue
  • 6
Page start
  • e1006124
Language
  • English
ISSN
  • 1553-7390
  • 1553-7404

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