SOS-independent prophage induction pathways and their contributions to antibiotic resistance gene dissemination: advances and controversies

Temperate bacteriophages integrate into bacterial chromosomes as prophages, which are widespread across sequenced bacterial genomes and serve as key mobile genetic elements mediating horizontal gene transfer and the global dissemination of antibiotic resistance genes (ARGs). For decades, prophage induction has been thought to rely almost entirely on the canonical SOS DNA damage response triggered by DNA-damaging agents such as fluoroquinolones and mitomycin C; however, accumulating experimental evidence shows that multiple SOS-independent regulatory circuits also drive the lysogeny-to-lysis switch in response to non-DNA-damaging physiological and environmental cues. In this mini-review, we classify SOS-independent prophage induction pathways into five major categories: quorum sensing-mediated regulation, metabolic and oxidative stress-triggered activation, induction by sub-inhibitory concentrations of non-DNA-damaging antibiotics, spontaneous induction driven by stochastic gene expression noise, and modulation by physiological and environmental factors such as bile acids and osmotic stress. We summarize the molecular basis of each pathway and examine available empirical evidence linking these induction routes to phage-mediated ARG dissemination across clinical, intestinal, and environmental microbial ecosystems. We further outline four core unresolved debates in the field: the relative quantitative contribution of SOS-independent versus SOS-dependent induction to resistance spread, the mechanistic classification of sub-inhibitory antibiotic effects, the gap between bioinformatic predictions of prophage-associated ARGs and their functional transmissibility, and the limited taxonomic scope of current mechanistic research. We conclude by discussing implications for antimicrobial resistance stewardship and highlighting priority directions for future quantitative and functional investigations.