Design of a broad-range bacteriophage cocktail that reduces Pseudomonas aeruginosa biofilms and treats acute infections in two animal models. [PublishAheadOfPrint]

The alarming diffusion of multidrug resistant (MDR) bacterial strains requires investigations on non-antibiotic therapies. Amongst them, the use of bacteriophages (phages) as antimicrobial agents, namely phage therapy, is a promising treatment strategy with support by recent successful compassionate treatments in Europe and the U.S.A. In this work, we combined host range and genomic information to design a 6-phage cocktail killing several clinical strains of P. aeruginosa, including those collected from Italian cystic fibrosis (CF) patients, and analyzed the cocktail performance. We demonstrated that the cocktail composed of four novel (PYO2, DEV, E215 and E217) and two previously characterized (PAK_P1 and PAK_P4) phages was able to lyse P. aeruginosa both in planktonic liquid cultures and in biofilm. In addition, we showed that the phage cocktail could cure acute respiratory infection in mouse and treat bacteremia in the wax moth Galleria mellonella larvae. Furthermore, administration of the cocktail to larvae prior to bacterial infection provided prophylaxis. In this regard, efficiency of the phage cocktail was found to be unaffected by the MDR or mucoid phenotype of the pseudomonal strain. The cocktail was found to be superior to individual phages in destroying biofilms and providing a faster treatment in mice. We also found the Galleria larvae model to be cost-effective for testing clinical strains susceptibility to phages, suggesting that it could be implemented in the frame of developing personalized phage therapies.

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