Conjugation as an evolutionary bottleneck in antimicrobial resistance spread

Antimicrobial resistance (AMR) is commonly framed as a consequence of mutation and selection, yet this perspective does not fully explain the speed and scale of global resistance dissemination. Here, we argue that AMR is better understood as an amplification problem, in which horizontal gene transfer particularly conjugation governs the spread of resistance genes across bacterial populations and ecological compartments. Conjugative plasmids couple high transfer efficiency with broad host range, enabling rapid dissemination of resistance determinants, including those conferring resistance to last-resort antibiotics. This review synthesizes evidence showing that conjugation is shaped by tightly constrained trade-offs between transfer efficiency, fitness cost, plasmid copy number, and ecological context. These constraints render conjugation a rate-limiting step in dissemination dynamics, such that even modest reductions in transfer efficiency can substantially reduce plasmid persistence and spread. At the same time, plasmids exhibit adaptive features, including compensatory evolution and dynamic regulation of replication, that stabilize their persistence and complicate intervention. This duality positions conjugation as both a central driver of AMR and a tractable therapeutic target. We review emerging strategies to disrupt conjugation, including small-molecule inhibitors, CRISPR-based systems, phage approaches, and ecological interventions, and highlight key challenges related to delivery, evolutionary escape, and real-world implementation. We propose that targeting gene flow rather than gene emergence alone offers a complementary strategy for controlling AMR. By reframing conjugation as a controllable bottleneck in resistance amplification, future interventions may shift the trajectory of AMR from expansion toward containment.