Immune-deficient bacteria serve as gateways to genetic exchange and microbial evolution.

Horizontal gene transfer plays a key role in bacterial evolution, yet its efficiency under natural conditions, especially between genetically distinct strains, remains unclear. Using Staphylococcus aureus as a model, we found that gene transfer via various mechanisms is significantly restricted between strains from different clonal complexes (CCs), with the notable exception of lateral transduction, which occurs at high frequency. Interestingly, some strains exhibited a promiscuous ability to accept diverse mobile genetic elements. These strains were defective in key immune defences, specifically the Type I restriction-modification systems that normally protect against foreign DNA. A broader analysis revealed that such immune-deficient mutants are widespread within S. aureus populations. Our study uncovered a trade-off that may account for their persistence in nature: although these mutants are more susceptible to phage attack, they gain an evolutionary advantage by acquiring new genes - such as those conferring antibiotic resistance - which would enhance survival under selective pressure. These immune-deficient cells act as gateways for foreign DNA, which, once integrated and advantageous, can spread within the same CC. Our findings highlight the role of immune-deficient bacteria in facilitating the emergence of novel virulence factors and antibiotic resistance, emphasising their importance in shaping bacterial evolution.