{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T16:01:55Z","timestamp":1792684915952,"version":"4.5.0"},"reference-count":158,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T00:00:00Z","timestamp":1786060800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antibiotics"],"abstract":"<jats:p>Background\/Objectives: Antimicrobial resistance among ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) pathogens has become a major global health threat, significantly reducing the effectiveness of conventional antibiotics. Plant-derived compounds have emerged as promising antibiotic adjuvants capable of restoring antibiotic activity through multiple resistance-modulating mechanisms. This review aims to critically evaluate the current evidence regarding phytochemicals that enhance antibiotic efficacy against drug-resistant ESKAPE pathogens. Methods: Relevant studies investigating plant-derived compounds with antibiotic adjuvant activity against ESKAPE pathogens were identified and critically analyzed. Particular attention was given to mechanisms of action, synergistic interactions with conventional antibiotics, structure\u2013activity relationships, and translational evidence from in vivo studies. Results: Numerous phytochemicals have demonstrated the ability to potentiate antibiotic activity through efflux pump inhibition, biofilm disruption, membrane permeabilization, and quorum sensing interference. For instance, the flavonoid quercetin inhibits the NorA efflux pump in Staphylococcus aureus, restoring ciprofloxacin susceptibility, while the sulfur-containing compound ajoene from garlic disrupts quorum sensing in Pseudomonas aeruginosa, sensitizing biofilms to tobramycin. Although several compounds exhibit promising synergistic effects in vitro, significant barriers remain regarding bioavailability, standardization, pharmacokinetics, and clinical translation. Conclusions: Plant-derived antibiotic adjuvants represent a promising strategy to combat multidrug-resistant ESKAPE pathogens. However, greater emphasis on translational research, standardized methodologies, and clinically relevant experimental models is required to facilitate their development toward therapeutic applications.<\/jats:p>","DOI":"10.3390\/antibiotics15080761","type":"journal-article","created":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T13:20:16Z","timestamp":1786108816000},"page":"761","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Plant-Derived Compounds as Antibiotic Adjuvants Against Drug-Resistant ESKAPE Pathogens: Mechanisms of Action, Synergistic Strategies, and Translational Challenges"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-0401-4027","authenticated-orcid":false,"given":"Stefano","family":"Ruga","sequence":"first","affiliation":[{"name":"Department of Health Sciences, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"Matarese","sequence":"additional","affiliation":[{"name":"Vita-Salute San Raffaele University, 20132 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9600-6401","authenticated-orcid":false,"given":"Fabio","family":"Castagna","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3007-8154","authenticated-orcid":false,"given":"Clementina","family":"Sansone","sequence":"additional","affiliation":[{"name":"Department of Eco-Sustainable Marine Biotechnologies, Anton Dohrn Zoological Station, Molosiglio Marina di Acton, 80133 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0587-8467","authenticated-orcid":false,"given":"Canio","family":"Martinelli","sequence":"additional","affiliation":[{"name":"Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, Department of Biology, College of Science and Technology, Temple University, Philadelphia, PA 19122, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulio","family":"Mazzarotti","sequence":"additional","affiliation":[{"name":"Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, Department of Biology, College of Science and Technology, Temple University, Philadelphia, PA 19122, USA"},{"name":"Sbarro Health Research Organization ETS, 10060 Candiolo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-7236-4830","authenticated-orcid":false,"given":"Andrea","family":"Russo","sequence":"additional","affiliation":[{"name":"Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, Department of Biology, College of Science and Technology, Temple University, Philadelphia, PA 19122, USA"},{"name":"Sbarro Health Research Organization ETS, 10060 Candiolo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annamaria","family":"Medugno","sequence":"additional","affiliation":[{"name":"Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, Department of Biology, College of Science and Technology, Temple University, Philadelphia, PA 19122, USA"},{"name":"Sbarro Health Research Organization ETS, 10060 Candiolo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shendi","family":"Shani","sequence":"additional","affiliation":[{"name":"Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, Department of Biology, College of Science and Technology, Temple University, Philadelphia, PA 19122, USA"},{"name":"Sbarro Health Research Organization ETS, 10060 Candiolo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5959-016X","authenticated-orcid":false,"given":"Antonio","family":"Giordano","sequence":"additional","affiliation":[{"name":"Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, Department of Biology, College of Science and Technology, Temple University, Philadelphia, PA 19122, USA"},{"name":"Department of Medical Biotechnologies, University of Siena, 53100 Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4173-8584","authenticated-orcid":false,"given":"Roberto","family":"Bava","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3031-345X","authenticated-orcid":false,"given":"Giovanna","family":"Liguori","sequence":"additional","affiliation":[{"name":"Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, Department of Biology, College of Science and Technology, Temple University, Philadelphia, PA 19122, USA"},{"name":"Sbarro Health Research Organization ETS, 10060 Candiolo, Italy"},{"name":"Local Health Authority of Foggia (ASL Foggia), 71121 Foggia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1038\/nrmicro3380","article-title":"Molecular mechanisms of antibiotic resistance","volume":"13","author":"Blair","year":"2015","journal-title":"Nat. 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