Pseudolysogeny-mediated evolutionary trade-offs favor phage therapy by limiting antibiotic resistance and virulence in <i>Cutibacterium acnes</i>

Abstract Phage therapy has mostly focused on strictly lytic phages, yet the ecological and evolutionary implications of pseudolysogeny remain poorly understood. Pseudolysogeny—where a phage genome persists in a non-integrated, latent state within the host—has been largely overlooked due to concerns about therapeutic efficacy. Here, we demonstrate that pseudolysogeny in Cutibacterium acnes confers superinfection resistance but imposes substantial fitness costs, including reduced biofilm formation, impaired interspecies competitiveness, and reversal of antibiotic resistance. Pseudolysogenic phages were also capable of killing starved C. acnes cells through direct lytic replication. No evidence of transduction of clindamycin resistance by these phages was detected. In a 3-month proof-of-concept study, topical application of a pseudolysogenic phage significantly reduced C. acnes abundance, acne lesions, and inflammation, with no adverse effects and persistence of viable phages post-treatment. Importantly, no phage-resistant C. acnes clones were detected during the in vivo study, likely due to the evolutionary trade-offs associated with pseudolysogeny that diminish the bacterial ecological fitness. These findings highlight pseudolysogeny as a mechanism that can be leveraged to enhance phage therapy outcomes while maintaining microbiome stability and limiting antibiotic resistance evolution.