Filtering the mobile resistome: how evolutionary trade-offs in bacterial immunity shapes antimicrobial resistance

Although antimicrobial resistance (AMR) is traditionally viewed as a consequence of antibiotic selection, growing evidence indicates that bacterial immune systems regulate which mobile genetic elements (MGEs) successfully enter, establish, and persist within bacterial populations. Here, we argue that bacterial immunity helps determine access to the mobile resistome and, consequently, shapes the evolutionary opportunities upon which antibiotic selection acts. This review synthesizes current evidence on the interplay between bacterial immunity, counter-defense mechanisms, and MGE-MGE conflict, highlighting how these interactions collectively influence the entry, survival, expression, persistence, and transmission of foreign DNA. We further discuss recent discoveries revealing a far greater diversity of bacterial defence and MGE counter-defence strategies than previously recognized, including conflicts extending beyond genome protection to the regulation of gene expression, and consider how this expanding molecular repertoire influences MGE accessibility and the mobile genetic variation available for AMR evolution. By integrating concepts that are typically discussed separately, we propose that immunity, counter-defense, and MGE competition collectively regulate access to the vast and largely uncatalogued mobile gene pool from which resistance determinants are acquired. Viewed through this framework, AMR emerges not only from antibiotic selection, but also from the evolutionary processes that determine which genetic variants become available for selection, providing a broader perspective on resistance emergence and the uneven distribution of high-risk resistant lineages.