{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T13:12:42Z","timestamp":1790082762579,"version":"4.0.1"},"reference-count":108,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T00:00:00Z","timestamp":1790035200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Higher Educational Institutions Youth Innovation Science and Technology Support Program of Shandong Province","award":["2023KJL004"],"award-info":[{"award-number":["2023KJL004"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82272751"],"award-info":[{"award-number":["82272751"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Microbiol."],"abstract":"<jats:p>\n                    Multidrug-resistant (MDR) Gram-negative bacteria\u2014particularly carbapenem-resistant Enterobacterales,\n                    <jats:italic>Pseudomonas aeruginosa<\/jats:italic>\n                    and\n                    <jats:italic>Acinetobacter baumannii<\/jats:italic>\n                    \u2014remain among the hardest infections to treat, and Resistance-Nodulation-Division (RND) efflux pumps are central to that resistance, making them a recurring target for antibiotic-adjuvant strategies. Natural products offer chemically diverse starting points for efflux-modulating adjuvants, but a fall in MIC is hard to attribute to pump inhibition: membrane permeabilisation, proton-motive-force (PMF) dissipation, efflux-gene downregulation, intrinsic antibacterial activity and general stress responses all give the same readout. We review natural product-derived and semisynthetic RND efflux pump inhibitor-like (EPI-like) candidates in Gram-negative bacteria, organising the evidence by target pump, potentiated antibiotic, proposed mechanism, strength of supporting data and translational feasibility. In place of chemical structures, candidates are read through mechanism-relevant structure-feature associations and the extent of pump-specific validation. Throughout, we separate three routinely conflated claims\u2014antibiotic synergy, functional efflux modulation and direct target binding\u2014and grade them with a pragmatic five-level scheme aimed at curbing over-reading of MIC-based synergy. One pattern dominates: synergy is reported widely, yet candidates reaching pump-associated validation are scarce, and higher-grade pump-dependent evidence remains concentrated on\n                    <jats:italic>Escherichia coli<\/jats:italic>\n                    AcrB. Camalexin is the clearest AcrB-dependent phenotype, but only provisionally\u2014a Level 4a grade resting on a single unreplicated study\u2014while plumbagin and nordihydroguaiaretic acid also reach provisional Level 4a because their potentiation and efflux phenotypes were AcrB-dependent and were not explained by outer-membrane permeabilisation. Direct target engagement remains unproven; the rare Level 4 cases beyond AcrB rely on a MexXY-OprM chemical probe or on expression change alone. Comparable pump-specific support for MexB, MexY and AdeB is largely absent. The proposed roadmap should therefore be viewed as an AcrB-anchored hypothesis that requires independent validation across these clinically important pumps. We propose a mechanism-informed structure-feature model and a staged validation roadmap coupling pump-specific strains, membrane and PMF controls, direct target engagement, feature-guided optimisation, cytotoxicity\/PK assessment and\n                    <jats:italic>in vivo<\/jats:italic>\n                    infection models.\n                  <\/jats:p>","DOI":"10.3389\/fmicb.2026.1915579","type":"journal-article","created":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T12:37:20Z","timestamp":1790080640000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["RND efflux pump inhibitor-like natural products as antibiotic adjuvants against multidrug-resistant gram-negative bacteria: a graded-evidence review"],"prefix":"10.3389","volume":"17","author":[{"given":"Danxia","family":"Kong","sequence":"first","affiliation":[{"name":"Department of Occupational Pulmonology, Shandong First Medical University Affiliated Occupational Disease Hospital (Shandong Province Hospital of Occupational Diseases), Shandong Academy of Occupational Health and Occupational Medicine","place":["Jinan, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baoyan","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Occupational Pulmonology, Shandong First Medical University Affiliated Occupational Disease Hospital (Shandong Province Hospital of Occupational Diseases), Shandong Academy of Occupational Health and Occupational Medicine","place":["Jinan, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingchen","family":"Ding","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences","place":["Jinan, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences","place":["Jinan, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,22]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"2271","DOI":"10.1093\/jac\/dkv111","article-title":"Enhanced efficacy of putative efflux pump inhibitor\/antibiotic combination treatments versus MDR strains of Pseudomonas aeruginosa in a galleria mellonella in vivo infection model","volume":"70","author":"Adamson","year":"2015","journal-title":"J. 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