The Future of Bacteriophage Therapy Will Promote Antimicrobial Susceptibility

Abstract

Rising antimicrobial resistance severely limits efforts to treat infections and is a cause for critical concern. Renewed interest in bacteriophage therapy has advanced understanding of the breadth of species capable of targeting bacterial antimicrobial resistance mechanisms, but many questions concerning ideal application remain unanswered. The following minireview examines bacterial resistance mechanisms, the current state of bacteriophage therapy, and how bacteriophage therapy can augment strategies to combat resistance with a focus on the clinically relevant bacterium Pseudomonas aeruginosa, as well as the role of efflux pumps in antimicrobial resistance. Methods to prevent antimicrobial efflux using efflux pump inhibitors and phage steering, a type of bacteriophage therapy, are also covered. The evolutionary context underlying antimicrobial resistance and the need to include theory in the ongoing development of bacteriophage therapy are also discussed.

Keywords: Pseudomonas aeruginosa; antibiotic resistance; bacteriophage therapy; evolutionary rescue.

FIG 1

Efflux pump inhibitor (EPI) mechanisms (A to D) compared to phage steering (E). The figure illustrates (A) substrate competition causing efflux of EPIs (black circles) while retaining antimicrobials (red circles), (B) altered antimicrobial structure by EPIs (red squares) prevents recognition by the efflux system, (C) disruption of pump assembly, (D) disruption of the proton motive force required for efflux, and (E) phage steering using the outer efflux protein as a receptor to block efflux in addition to actively destroying pathogens.