Unlocking the Next Generation of Phage Therapy: the Key is in the Receptors

Phage therapy, the clinical use of viruses that kill bacteria, is a promising strategy in the fight against antimicrobial resistance. Before administration, phages undergo a careful examination of their safety and interactions with target bacteria. This characterization seldom includes identifying the receptor on the bacterial surface involved in phage adsorption. In this perspective article, we propose that understanding the function and location of these phage receptors can open the door to improved and innovative ways to use phage therapy. With knowledge of phage receptors, we can design intelligent phage cocktails, discover new phage-derived antimicrobials, and steer the evolution of phage-resistance towards clinically exploitable phenotypes. In an effort to jump-start this initiative, we recommend priority groups of hosts and phages. Finally, we review modern approaches for the identification of phage receptors, including molecular platforms for high-throughput mutagenesis, synthetic biology, and machine learning.