{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:57:17Z","timestamp":1792789037506,"version":"4.5.0"},"reference-count":38,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T00:00:00Z","timestamp":1789689600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Institute of Chemical Biology and Fundamental Medicine SB RAS","award":["121031300042\u20131"],"award-info":[{"award-number":["121031300042\u20131"]}],"id":[{"id":"https:\/\/ror.org\/00gmz2d02","id-type":"ROR","asserted-by":"crossref"}]},{"award":["121031300042\u20131"],"award-info":[{"award-number":["121031300042\u20131"]}],"id":[{"id":"https:\/\/ror.org\/00gmz2d02","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antibiotics"],"abstract":"<jats:p>Background\/Objectives: The rapid emergence and spread of antibiotic-resistant bacterial strains represent a major global health threat, requiring the development of novel broad-spectrum antimicrobial agents. This study aims to design, synthesize, and evaluate a novel series of multitarget amphiphilic carvacrol derivatives to combat molecular resistance mechanisms by combining a natural monoterpene with polycationic ribonuclease scaffolds. Methods: A series of 16 dimeric carvacrol\u20131,4-diazabicyclo[2.2.2]octane (DABCO) hybrids, including both novel and previously reported derivatives, with varying central and lateral linkers were synthesized. In vitro antibacterial activity was evaluated against Gram-positive (S. aureus) and Gram-negative (E. coli, S. enterica, C. freundii, P. aeruginosa, A. baumannii) strains. Antibacterial action was examined through a time-kill kinetic assay against S. aureus at minimum inhibitory concentrations (MICs). RNA-hydrolyzing efficiency (using a FAM-labeled 17-mer ribooligonucleotide), hemolytic activity on rabbit red blood cells, and cytotoxicity (MTT assay) against RPMI8226, LMTK, and MEF cell lines were assessed. Results: Several compounds exhibited potent antibacterial activity, with MIC values ranging from 4 to 63 \u00b5M against most strains. The most active hybrid, DL4CAR-6, demonstrated broad-spectrum efficacy (MIC 4\u201316 \u00b5M against most strains) and outperformed the reference amphiphile DL4-12 against P. aeruginosa eightfold. Bacterial growth inhibition kinetic assay revealed that the cationic amphiphiles eradicate S. aureus faster than the reference antibiotic, indicating rapid membrane disruption. Most hybrids demonstrated pronounced RNA-hydrolyzing activity (up to 60% cleavage). The hemolytic assay showed less than 10% hemolysis for most compounds even at 500 \u00b5M. Furthermore, DL4CAR-6 displayed low cytotoxicity (IC50 114\u2013250 \u00b5M), with safety thresholds exceeding effective antibacterial doses. Conclusions: The newly developed carvacrol\u2013DABCO amphiphilic hybrids represent a promising class of multitarget antibacterial agents. Their broad-spectrum efficacy, bactericidal kinetics, RNA-cleaving activity, low hemolytic toxicity, and favorable selectivity indices support their potential for further in vivo evaluation.<\/jats:p>","DOI":"10.3390\/antibiotics15090927","type":"journal-article","created":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T15:28:43Z","timestamp":1790090923000},"page":"927","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Synthesis and In Vitro Biological Evaluation of Amphiphilic Derivatives of Carvacrol as Potent Antibacterial Agents"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7997-3144","authenticated-orcid":false,"given":"Danila A.","family":"Zadvornykh","sequence":"first","affiliation":[{"name":"Knorre Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of Russian Academy of Sciences, Lavrentiev Avenue 8, Novosibirsk 630090, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meiling","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Life and Health Sciences, Fuyao University of Science and Technology, Zhihui Avenue 104, Fuzhou 350109, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"}]},{"given":"Alevtina V.","family":"Bardasheva","sequence":"additional","affiliation":[{"name":"Knorre Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of Russian Academy of Sciences, Lavrentiev Avenue 8, Novosibirsk 630090, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna S.","family":"Pavlova","sequence":"additional","affiliation":[{"name":"Knorre Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of Russian Academy of Sciences, Lavrentiev Avenue 8, Novosibirsk 630090, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga D.","family":"Zakharova","sequence":"additional","affiliation":[{"name":"Knorre Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of Russian Academy of Sciences, Lavrentiev Avenue 8, Novosibirsk 630090, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena V.","family":"Dmitrienko","sequence":"additional","affiliation":[{"name":"Knorre Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of Russian Academy of Sciences, Lavrentiev Avenue 8, Novosibirsk 630090, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lyudmila S.","family":"Koroleva","sequence":"additional","affiliation":[{"name":"Knorre Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of Russian Academy of Sciences, Lavrentiev Avenue 8, Novosibirsk 630090, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9179-4787","authenticated-orcid":false,"given":"Wei","family":"Xie","sequence":"additional","affiliation":[{"name":"School of Life and Health Sciences, Fuyao University of Science and Technology, Zhihui Avenue 104, Fuzhou 350109, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"}]},{"given":"Vladimir N.","family":"Silnikov","sequence":"additional","affiliation":[{"name":"Knorre Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of Russian Academy of Sciences, Lavrentiev Avenue 8, Novosibirsk 630090, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Urban-Chmiel, R., Marek, A., St\u0119pie\u0144-Py\u015bniak, D., Wieczorek, K., Dec, M., Nowaczek, A., and Osek, J. 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