Anti-Quorum Sensing Phages Disarm Pseudomonas aeruginosa

Abstract By 2050, the death toll from previously preventable or easily curable bacterial infections is projected to surpass that caused by cancer, unless we prevent the spread of antibiotic resistance and develop new therapies. A promising approach is phage therapy, which exploits bacteriophages, natural predators of bacteria. However, bacteria fight back, which can limit its efficacy. Notably, many bacteria rely on cell-cell communication, known as quorum sensing, to orchestrate both virulence programs and phage defenses. To circumvent these, we have engineered anti-quorum sensing phages against the human pathogen Pseudomonas aeruginosa . Our engineered phages effectively degrade quorum-sensing molecules, reduce virulence factor production, and double the survival of P. aeruginosa -infected Galleria mellonella larvae. Moreover, we demonstrate that the anti-quorum sensing phages inhibit quorum sensing in mixed populations of phage-susceptible and phage-resistant cells, demonstrating the ability of the phages to disarm subpopulations phage-resistant P. aeruginosa , which often are selected for during phage treatment. Together, our findings highlight the future therapeutic promise of anti-quorum sensing phages as a dual-action strategy in killing susceptible cells while attenuating virulence across the bacterial population. This approach has the potential to enhance the robustness of phage therapy.