{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T06:35:26Z","timestamp":1776926126900,"version":"3.51.2"},"reference-count":108,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T00:00:00Z","timestamp":1776902400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Microbiol."],"abstract":"<jats:p>\n                    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 \u201cbactericidal\u201d antibiotic strategies impose strong selective pressure, failing to eradicate the root cause of resistance while accelerating the enrichment of resistant clones. \u201cPlasmid curing\u201d\u2014a strategy that specifically eliminates resistance plasmids to restore antibiotic susceptibility\u2014has 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\u2014from high-throughput screening to absolute quantitative PCR\u2014necessary to strictly differentiate true\n                    <jats:italic>in vivo<\/jats:italic>\n                    plasmid curing from mere selective bactericidal artifacts. Furthermore, we address current translational bottlenecks, particularly the \u201ctherapeutic window paradox,\u201d 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 \u201cbacterial killing\u201d to ecologically intelligent \u201cgenetic disarmament,\u201d natural plasmid-curing agents offer a vital, adjunctive solution for safeguarding the lifespan of legacy antibiotics.\n                  <\/jats:p>","DOI":"10.3389\/fmicb.2026.1802582","type":"journal-article","created":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T05:36:17Z","timestamp":1776922577000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Beyond bactericidal: targeting plasmid-mediated antibiotic resistance with natural product-based plasmid curing agents"],"prefix":"10.3389","volume":"17","author":[{"given":"Jia","family":"Wang","sequence":"first","affiliation":[{"name":"Heilongjiang University of Chinese Medicine","place":["Harbin, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qun","family":"Liang","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital of Heilongjiang University of Chinese Medicine","place":["Harbin, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,4,23]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"1496","DOI":"10.1099\/mic.0.001496","article-title":"Natural products from food sources can alter the spread of antimicrobial resistance plasmids in Enterobacterales","volume":"170","author":"Alav","year":"2024","journal-title":"Microbiology"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"201","DOI":"10.3389\/fmolb.2020.00201","article-title":"Type iv coupling proteins as potential targets to control the dissemination of antibiotic resistance","volume":"7","author":"\u00c1lvarez-Rodr\u00edguez","year":"2020","journal-title":"Front. 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