title: Personalized Therapeutic Cocktail of Wild Environmental Phages Rescues Mice from Acinetobacter baumannii Wound Infections.
abstract: Multidrug-resistant bacterial pathogens are an increasing threat to public health, and lytic bacteriophages have reemerged as a potential therapeutic option. In this work, we isolated and assembled a five-member cocktail of wild phages against Acinetobacter baumannii and demonstrated therapeutic efficacy in a mouse full-thickness dorsal infected wound model. The cocktail lowers the bioburden in the wound, prevents the spread of infection and necrosis to surrounding tissue, and decreases infection-associated morbidity. Interestingly, this effective cocktail is composed of four phages that do not kill the parent strain of the infection and one phage that simply delays bacterial growth in vitro via a strong but incomplete selection event. The cocktail here appears to function in a combinatorial manner, as one constituent phage targets capsulated A. baumannii bacteria and selects for loss of receptor, shifting the population to an uncapsulated state that is then sensitized to the remaining four phages in the cocktail. Additionally, capsule is a known virulence factor for A. baumannii, and we demonstrated that the emergent uncapsulated bacteria are avirulent in a Galleria mellonella model. These results highlight the importance of anticipating population changes during phage therapy and designing intelligent cocktails to control emergent strains, as well as the benefits of using phages that target virulence factors. Because of the efficacy of this cocktail isolated from a limited environmental pool, we have established a pipeline for developing new phage therapeutics against additional clinically relevant multidrug-resistant pathogens by using environmental phages sourced from around the globe.
authors.affiliation: Wound Infections Department, Naval Medical Research Center, Silver Spring, Maryland, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Regeimbal
authors.affiliation: Wound Infections Department, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA.
authors.forename: Anna C
authors.initials: AC
authors.lastname: Jacobs
authors.affiliation: Wound Infections Department, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA.
authors.forename: Brendan W
authors.initials: BW
authors.lastname: Corey
authors.affiliation: Biological Defense Research Directorate, Naval Medical Research Center-Frederick, Fort Detrick, Maryland, USA.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Henry
authors.affiliation: Wound Infections Department, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA.
authors.forename: Mitchell G
authors.initials: MG
authors.lastname: Thompson
authors.affiliation: Wound Infections Department, Naval Medical Research Center, Silver Spring, Maryland, USA.
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Pavlicek
authors.affiliation: Biological Defense Research Directorate, Naval Medical Research Center-Frederick, Fort Detrick, Maryland, USA.
authors.forename: Javier
authors.initials: J
authors.lastname: Quinones
authors.affiliation: National Bioforensic Analysis Center, National Biodefense and Countermeasures Center, Fort Detrick, Maryland, USA.
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Hannah
authors.affiliation: Regenerative Medicine Department, Naval Medical Research Center, Silver Spring, Maryland, USA.
authors.forename: Meron
authors.initials: M
authors.lastname: Ghebremedhin
authors.affiliation: Regenerative Medicine Department, Naval Medical Research Center, Silver Spring, Maryland, USA.
authors.forename: Nicole J
authors.initials: NJ
authors.lastname: Crane
authors.affiliation: Wound Infections Department, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA.
authors.forename: Daniel V
authors.initials: DV
authors.lastname: Zurawski
authors.affiliation: Wound Infections Department, Naval Medical Research Center, Silver Spring, Maryland, USA.
authors.forename: Nimfa C
authors.initials: NC
authors.lastname: Teneza-Mora
authors.affiliation: Biological Defense Research Directorate, Naval Medical Research Center-Frederick, Fort Detrick, Maryland, USA biswas.biswajit.ctr@mail.mil.
authors.forename: Biswajit
authors.initials: B
authors.lastname: Biswas
authors.affiliation: Wound Infections Department, Naval Medical Research Center, Silver Spring, Maryland, USA.
authors.forename: Eric R
authors.initials: ER
authors.lastname: Hall
mesh_terms: D000151:Acinetobacter Infections / Q000628:therapy* / Q000821:virology; D040981:Acinetobacter baumannii / Q000737:chemistry / Q000472:pathogenicity / Q000821:virology*; D000818:Animals; D001435:Bacteriophages; D024901:Drug Resistance, Multiple, Bacterial; D005260:Female; D008807:Mice, Inbred BALB C; D009036:Moths / Q000382:microbiology; D012722:Sewage / Q000821:virology; D013059:Spectrum Analysis, Raman; D014946:Wound Infection / Q000628:therapy* / Q000821:virology
chemical_list: D012722:Sewage