Beyond bactericidal: targeting plasmid-mediated antibiotic resistance with natural product-based plasmid curing agents

Antimicrobial resistance (AMR) has evolved into a severe global public health crisis, with plasmid-mediated horizontal gene transfer (HGT) serving as a core driver for the rapid dissemination of multidrug resistance (MDR). Traditional "bactericidal" antibiotic strategies impose strong selective pressure, failing to eradicate the root cause of resistance while accelerating the enrichment of resistant clones. "Plasmid curing"-a strategy that specifically eliminates resistance plasmids to restore antibiotic susceptibility-has emerged as a promising paradigm shift. While early synthetic curing agents suffered from severe cytotoxicity, natural products (e.g., alkaloids, quinones, terpenoids) exhibit unique potential owing to their structural diversity and multi-target profiles. This review systematically elucidates the molecular mechanisms by which natural products achieve plasmid eradication, including the disruption of Rep-ori replication initiation, interference with ParA-ParB partitioning dynamics, and the blockade of conjugation via type IV secretion system (T4SS) and quorum sensing (QS) inhibition. Crucially, we critically evaluate the methodological workflows-from high-throughput screening to absolute quantitative PCR-necessary to strictly differentiate true in vivo plasmid curing from mere selective bactericidal artifacts. Furthermore, we address current translational bottlenecks, particularly the "therapeutic window paradox," and highlight how integrating advanced nanotechnology, artificial intelligence (AI)-guided drug discovery, and CRISPR-Cas9 synergies will propel the field forward. By shifting the therapeutic paradigm from violent "bacterial killing" to ecologically intelligent "genetic disarmament," natural plasmid-curing agents offer a vital, adjunctive solution for safeguarding the lifespan of legacy antibiotics.