Stage-Specific Strategies to Limit the Spread of Antibiotic Resistance in Bacteria with a Focus on Conjugation

Abstract

Horizontal gene transfer (HGT) is the main reason for antibiotic resistance evolution, enabling bacteria to obtain resistance determinants far more rapidly than through point mutations alone. Among HGT mechanisms, conjugation plays a particularly critical role for its efficiency, broad host range, and capacity in disseminating complex resistance plasmids across microbial communities. Despite its clinical significance, conjugation has remained an under-explored target for antimicrobial intervention. This research aims to provide an integrated analysis of bacterial conjugation within the broader context of HGT, emphasizing its evolutionary persistence and mechanistic vulnerabilities. Evidence is synthesized from molecular biology, experimental evolution, and population genetics to uphold the argument for the maintenance of plasmid-mediated resistance through a balance of transfer efficiency, compensatory adaptations, and post-transfer stabilization mechanisms. Building on this foundation, a stage-specific framework is proposed for disrupting conjugation by targeting pre-transfer cell-cell contact, peri-transfer DNA processing, and post-transfer plasmid maintenance. Multiple intervention strategies are reviewed and evaluated in this study, including conjugation inhibitors, relaxase-targeting compounds, CRISPR-based barriers, plasmid curing compounds, restriction-modification systems, as well as the plasmid addiction modules. Collectively, these approaches demonstrate that plasmid persistence is an evolvable trait that can be subjected to targeted interference. Overall, this study highlights conjugation-specific interfering strategies as a potential opportunity in slowing down resistance dissemination and preserving the efficacy of existing antibiotics.