title: Temperate and lytic bacteriophages programmed to sensitize and kill antibiotic-resistant bacteria.
abstract: 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.
authors.affiliation: Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Ido
authors.initials: I
authors.lastname: Yosef
authors.affiliation: Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Miriam
authors.initials: M
authors.lastname: Manor
authors.affiliation: Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Ruth
authors.initials: R
authors.lastname: Kiro
authors.affiliation: Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel ehudq@post.tau.ac.il.
authors.forename: Udi
authors.identifier: http://orcid.org/0000-0003-2169-5270
authors.initials: U
authors.lastname: Qimron
mesh_terms: D001419:Bacteria / Q000235:genetics / Q000821:virology*; D001435:Bacteriophages / Q000502:physiology*; D064112:Clustered Regularly Interspaced Short Palindromic Repeats; D024881:Drug Resistance, Bacterial; D008242:Lysogeny; D010957:Plasmids
keywords: CRISPR-Cas; ex vivo treatment; lysogenization; positive selection