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Title: 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. As a result, the loss of uptake may be an underappreciated mechanism for the development of kasugamycin resistance in bacterial plant pathogens.
Authors:
 [1] ; ORCiD logo [1] ;  [2] ;  [3] ;  [4] ;  [2] ; ORCiD logo [5] ;  [6]
  1. Univ. of California, San Francisco, CA (United States)
  2. European Molecular Biology Lab., Heidelberg (Germany)
  3. Univ. of North Carolina-Chapel Hill, Chapel, Hill, NC (United States)
  4. California Institute for Quantitative Biosciences, San Francisco, CA (United States); Univ. of California, San Francisco, CA (United States); Gladstone Institutes, San Francisco, CA (United States)
  5. Univ. of California, San Francisco, CA (United States); California Institute for Quantitative Biosciences, San Francisco, CA (United States)
  6. Uppsala Univ. (Sweden)
Publication Date:
Grant/Contract Number:
Graduate Fellowship
Type:
Published Article
Journal Name:
PLoS Genetics
Additional Journal Information:
Journal Volume: 12; Journal Issue: 6; Journal ID: ISSN 1553-7404
Publisher:
Public Library of Science
Research Org:
Office of Scientific and Technical Information, Oak Ridge, TN (United States)
Sponsoring Org:
USDOE
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES
OSTI Identifier:
1337762
Alternate Identifier(s):
OSTI ID: 1376695