High-frequency transposition for determining antibacterial mode of action

Nat Chem Biol. 2011 Sep 4;7(10):720-9. doi: 10.1038/nchembio.643.

Abstract

Connecting bacterial growth inhibitors to molecular targets at the whole-cell level is a major impediment to antibacterial development. Herein we report the design of a highly efficient and versatile bacteriophage-based mariner transposon delivery system in Staphylococcus aureus for determining inhibitor mode of action. Using bacteriophage-mediated delivery of concatameric minitransposon cassettes, we generated nonclonal transposant libraries with genome-wide insertion-site coverage in either laboratory or methicillin-resistant strain backgrounds and screened for drug resistance in situ on a single agar plate in one step. A gradient of gene-target expression levels, along with a correspondingly diverse assortment of drug-resistant phenotypes, was achieved by fitting the transposon cassette with a suite of outward-facing promoters. Using a panel of antibiotics, we demonstrate the ability to unveil not only an inhibitor's molecular target but also its route of cellular entry, efflux susceptibility and other off-target resistance mechanisms.

MeSH terms

  • Anti-Bacterial Agents / pharmacology*
  • Bacteriophages / genetics
  • Bacteriophages / physiology
  • DNA Transposable Elements / genetics*
  • Methicillin / pharmacology
  • Methicillin Resistance / genetics
  • Microbial Sensitivity Tests
  • Molecular Structure
  • Promoter Regions, Genetic / genetics
  • Staphylococcus aureus / drug effects*
  • Staphylococcus aureus / genetics*
  • Staphylococcus aureus / virology
  • Stereoisomerism
  • Transformation, Bacterial*

Substances

  • Anti-Bacterial Agents
  • DNA Transposable Elements
  • Methicillin