Tandem mobilization of anti-phage defenses alongside SCCmec cassettes

Bacterial viruses (phages) and the immune systems targeted against them significantly impact bacterial survival, evolution, and the emergence of pathogenic strains. While recent research has made spectacular strides towards discovering and validating new defenses in a few model organisms^1-3, the inventory of immune systems in clinically-relevant bacteria remains underexplored, and little is known about the mechanisms by which these systems horizontally spread. Such pathways not only impact the evolutionary trajectory of bacterial pathogens, but also threaten to undermine the effectiveness of phage-based therapeutics. Here, we investigate the battery of defenses in staphylococci, opportunistic pathogens that constitute leading causes of antibiotic-resistant infections. We show that these organisms harbor a variety of anti-phage defenses encoded within/near the infamous SCC (staphylococcal cassette chromosome) mec cassettes, mobile genomic islands that confer methicillin resistance. Importantly, we demonstrate that SCCmec-encoded recombinases mobilize not only SCCmec, but also tandem cassettes enriched with diverse defenses. Further, we show that phage infection potentiates cassette mobilization. Taken together, our findings reveal that beyond spreading antibiotic resistance, SCCmec cassettes play a central role in disseminating anti-phage defenses. This work underscores the urgent need for developing adjunctive treatments that target this pathway to save the burgeoning phage therapeutics from suffering the same fate as conventional antibiotics.