| Autor: |
Regeimbal JM; Wound Infections Department, Naval Medical Research Center, Silver Spring, Maryland, USA., Jacobs AC; Wound Infections Department, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA., Corey BW; Wound Infections Department, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA., Henry MS; Biological Defense Research Directorate, Naval Medical Research Center-Frederick, Fort Detrick, Maryland, USA., Thompson MG; Wound Infections Department, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA., Pavlicek RL; Wound Infections Department, Naval Medical Research Center, Silver Spring, Maryland, USA., Quinones J; Biological Defense Research Directorate, Naval Medical Research Center-Frederick, Fort Detrick, Maryland, USA., Hannah RM; National Bioforensic Analysis Center, National Biodefense and Countermeasures Center, Fort Detrick, Maryland, USA., Ghebremedhin M; Regenerative Medicine Department, Naval Medical Research Center, Silver Spring, Maryland, USA., Crane NJ; Regenerative Medicine Department, Naval Medical Research Center, Silver Spring, Maryland, USA., Zurawski DV; Wound Infections Department, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA., Teneza-Mora NC; Wound Infections Department, Naval Medical Research Center, Silver Spring, Maryland, USA., Biswas B; Biological Defense Research Directorate, Naval Medical Research Center-Frederick, Fort Detrick, Maryland, USA biswas.biswajit.ctr@mail.mil., Hall ER; Wound Infections Department, Naval Medical Research Center, Silver Spring, Maryland, USA. |
| Abstrakt: |
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. |
