{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T12:15:51Z","timestamp":1784290551213,"version":"3.55.0"},"reference-count":38,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T00:00:00Z","timestamp":1773619200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Antimicrobial resistance (AMR) is one of the most pressing global public health challenges, compromising the effectiveness of standard antibiotic therapies and increasing morbidity, mortality, and healthcare costs. The scarcity of new antibiotics has driven research into alternative strategies to restore or enhance the effectiveness of existing drugs. Natural compounds, including polyphenols, alkaloids, terpenes and terpenoids, antimicrobial peptides, and microbial secondary metabolites, exhibit multitarget activities such as membrane disruption, efflux pump inhibition, biofilm suppression, and quorum sensing interference. In parallel, synthetic and semi-synthetic small-molecule inhibitors have been rationally designed to target specific resistance determinants, including \u03b2-lactamases, efflux systems, quorum sensing pathways, and stress-induced mutagenesis mechanisms such as the SOS response and DNA repair processes. These agents act as adjuvants, restoring susceptibility or reducing bacterial virulence without exerting strong selective pressure. The integration of natural bioactive compounds and targeted small-molecule inhibitors represents a promising complementary strategy for conventional antibiotics. Further pharmacological and clinical investigations are required to translate these approaches into effective tools within antimicrobial stewardship programs and broader public health strategies aimed at mitigating the global burden of AMR. This narrative review analyses the recent literature on natural compounds and synthetic or semi-synthetic small-molecule inhibitors with documented activity against antimicrobial resistance mechanisms.<\/jats:p>","DOI":"10.3390\/ijms27062702","type":"journal-article","created":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T13:32:07Z","timestamp":1773667927000},"page":"2702","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["From Polyphenols to \u03b2-Lactamases: Multitarget Strategies to Defeat Severe Resistance"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-2378-2032","authenticated-orcid":false,"given":"Michele","family":"Nappa","sequence":"first","affiliation":[{"name":"Department of Medicine, Surgery and Dentistry \u201cScuola Medica Salernitana\u201d, University of Salerno, 84081 Salerno, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0602-2513","authenticated-orcid":false,"given":"Emanuela","family":"Santoro","sequence":"additional","affiliation":[{"name":"Department of Medicine, Surgery and Dentistry \u201cScuola Medica Salernitana\u201d, University of Salerno, 84081 Salerno, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberta","family":"Manente","sequence":"additional","affiliation":[{"name":"San Giovanni di Dio e Ruggi d\u2019Aragona University Hospital, 84081 Salerno, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6858-4362","authenticated-orcid":false,"given":"Angelo","family":"Cianciulli","sequence":"additional","affiliation":[{"name":"Department of Medicine, Surgery and Dentistry \u201cScuola Medica Salernitana\u201d, University of Salerno, 84081 Salerno, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7017-7413","authenticated-orcid":false,"given":"Giuseppina","family":"Moccia","sequence":"additional","affiliation":[{"name":"Department of Medicine, Surgery and Dentistry \u201cScuola Medica Salernitana\u201d, University of Salerno, 84081 Salerno, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9659-9940","authenticated-orcid":false,"given":"Francesco","family":"De Caro","sequence":"additional","affiliation":[{"name":"Department of Medicine, Surgery and Dentistry \u201cScuola Medica Salernitana\u201d, University of Salerno, 84081 Salerno, Italy"},{"name":"Public Health Laboratory for the Analysis of Community Health Needs, Department of Medicine and Surgery, University of Salerno, Baronissi Campus, 84081 Baronissi, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"Capunzo","sequence":"additional","affiliation":[{"name":"Department of Medicine, Surgery and Dentistry \u201cScuola Medica Salernitana\u201d, University of Salerno, 84081 Salerno, Italy"},{"name":"Integrated Care Department of Health Hygiene and Evaluative Medicine, San Giovanni di Dio e Ruggi d\u2019Aragona University Hospital, 84131 Salerno, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7757-6855","authenticated-orcid":false,"given":"Giovanni","family":"Boccia","sequence":"additional","affiliation":[{"name":"Department of Medicine, Surgery and Dentistry \u201cScuola Medica Salernitana\u201d, University of Salerno, 84081 Salerno, Italy"},{"name":"Integrated Care Department of Health Hygiene and Evaluative Medicine, San Giovanni di Dio e Ruggi d\u2019Aragona University Hospital, 84131 Salerno, Italy"},{"name":"Hospital and Epidemiological Hygiene Unit, San Giovanni di Dio e Ruggi d\u2019Aragona University Hospital, 84131 Salerno, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.3934\/microbiol.2025045","article-title":"Mechanisms of antimicrobial resistance: From genetic evolution to clinical manifestations","volume":"11","author":"Nusrat","year":"2025","journal-title":"AIMS Microbiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"886","DOI":"10.1001\/archinte.1991.00400050040010","article-title":"Mechanisms of bacterial resistance to antibiotics","volume":"151","author":"Dever","year":"1991","journal-title":"Arch. 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