Temperate and lytic bacteriophages programmed to sensitize and kill antibiotic-resistant bacteria

Proc Natl Acad Sci U S A. 2015 Jun 9;112(23):7267-72. doi: 10.1073/pnas.1500107112. Epub 2015 May 18.


The increasing threat of pathogen resistance to antibiotics requires the development of novel antimicrobial strategies. Here we present a proof of concept for a genetic strategy that aims to sensitize bacteria to antibiotics and selectively kill antibiotic-resistant bacteria. We use temperate phages to deliver a functional clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated (Cas) system into the genome of antibiotic-resistant bacteria. The delivered CRISPR-Cas system destroys both antibiotic resistance-conferring plasmids and genetically modified lytic phages. This linkage between antibiotic sensitization and protection from lytic phages is a key feature of the strategy. It allows programming of lytic phages to kill only antibiotic-resistant bacteria while protecting antibiotic-sensitized bacteria. Phages designed according to this strategy may be used on hospital surfaces and hand sanitizers to facilitate replacement of antibiotic-resistant pathogens with sensitive ones.

Keywords: CRISPR-Cas; ex vivo treatment; lysogenization; positive selection.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bacteria / genetics
  • Bacteria / virology*
  • Bacteriophages / physiology*
  • Clustered Regularly Interspaced Short Palindromic Repeats
  • Drug Resistance, Bacterial*
  • Lysogeny
  • Plasmids