title: Phage selection restores antibiotic sensitivity in MDR Pseudomonas aeruginosa.
abstract: Increasing prevalence and severity of multi-drug-resistant (MDR) bacterial infections has necessitated novel antibacterial strategies. Ideally, new approaches would target bacterial pathogens while exerting selection for reduced pathogenesis when these bacteria inevitably evolve resistance to therapeutic intervention. As an example of such a management strategy, we isolated a lytic bacteriophage, OMKO1, (family Myoviridae) of Pseudomonas aeruginosa that utilizes the outer membrane porin M (OprM) of the multidrug efflux systems MexAB and MexXY as a receptor-binding site. Results show that phage selection produces an evolutionary trade-off in MDR P. aeruginosa, whereby the evolution of bacterial resistance to phage attack changes the efflux pump mechanism, causing increased sensitivity to drugs from several antibiotic classes. Although modern phage therapy is still in its infancy, we conclude that phages, such as OMKO1, represent a new approach to phage therapy where bacteriophages exert selection for MDR bacteria to become increasingly sensitive to traditional antibiotics. This approach, using phages as targeted antibacterials, could extend the lifetime of our current antibiotics and potentially reduce the incidence of antibiotic resistant infections.
authors.affiliation: Department of Ecology and Evolutionary Biology, Yale University, New Haven, CT 06520, USA.
authors.forename: Benjamin K
authors.initials: BK
authors.lastname: Chan
authors.affiliation: School of Natural Sciences, University of California Merced, Merced, CA, 95343, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Sistrom
authors.affiliation: E. coli Genetic Stock Center, Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT 06520, USA.
authors.forename: John E
authors.initials: JE
authors.lastname: Wertz
authors.affiliation: Department of Microbial Pathogenesis, Yale School of Medicine, New Haven, CT 06520, USA.
authors.forename: Kaitlyn E
authors.initials: KE
authors.lastname: Kortright
authors.affiliation: Department of Surgery, Yale School of Medicine, New Haven, CT 06520, USA.
authors.forename: Deepak
authors.initials: D
authors.lastname: Narayan
authors.affiliation: Department of Ecology and Evolutionary Biology, Yale University, New Haven, CT 06520, USA.|Program in Microbiology, Yale School of Medicine, New Haven, CT 06520, USA.
authors.forename: Paul E
authors.initials: PE
authors.lastname: Turner
mesh_terms: D001425:Bacterial Outer Membrane Proteins / Q000235:genetics / Q000378:metabolism; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D017900:Myoviridae / Q000235:genetics / Q000378:metabolism; D011550:Pseudomonas aeruginosa / Q000235:genetics / Q000378:metabolism / Q000821:virology
chemical_list: D001425:Bacterial Outer Membrane Proteins; D001426:Bacterial Proteins; D026901:Membrane Transport Proteins; C118598:MexA protein, Pseudomonas aeruginosa; C118597:MexB protein, Pseudomonas aeruginosa; C402791:MexXY protein, Pseudomonas aeruginosa; C402263:OprM protein, Pseudomonas aeruginosa