Inhibiting horizontal gene transfer to contain antimicrobial resistance: conjugation and plasmid maintenance as druggable targets

Introduction Antimicrobial resistance (AMR) is propelled by horizontal gene transfer (HGT), with conjugative plasmids enabling rapid, cross-species spread and stable carriage of resistance. Interventions that reduce plasmid transmission or persistence can complement bactericidal therapies and infection-control programs.Areas covered We review druggable vulnerabilities in conjugation (mating-pair formation, type IV secretion/ATPase motors, coupling proteins, and relaxosome functions) and in plasmid maintenance (replication, partition, and toxin – antitoxin enforcement). The review is grounded in a narrative search of recent mechanistic, ecological, and in vivo literature. We cover biological antagonists (exclusion, fertility inhibition, and host defenses), chemical and metabolic inhibitors, and genetic strategies that repress transfer functions or selectively eliminate resistance elements.Expert opinion HGT inhibition is moving from proof-of-concept to actionable containment, but progress depends on mechanism-confirmed leads, standardized transfer metrics, plasmid confirmation, and safety evaluation in complex microbiomes and environments. Near-term impact is most likely as an adjunct to stewardship and infection prevention, aiming to reduce new acquisition and shorten carriage of high-risk resistance plasmids.