{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T09:03:35Z","timestamp":1785488615748,"version":"3.56.0"},"reference-count":82,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T00:00:00Z","timestamp":1785456000000},"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 peptides are promising agents for combating resistant infections. They exhibit bactericidal activity against a wide range of microbes, primarily by disrupting the permeability of the bacterial membrane and ultimately causing cell death. Effective bacterial killing requires a high number of membrane-bound peptide molecules. Therefore, it is conceivable that peptide accumulation on the membrane could also interfere with essential cellular processes by altering bilayer dynamics, a hypothesis referred to as the \u201csand-in-a-gearbox\u201d model. Methods: We systematically investigated how membrane dynamics is affected by a set of well-characterized yet highly diverse peptides: the natural AMP magainin 2, the toxin melittin, the synthetic peptides LAH4 and Killer-FLIP, and small membrane-active peptidomimetics with bactericidal activity. These effects were examined using fluorescence spectroscopy techniques, by measuring anisotropy, generalized polarization, and excimer formation of specific probes inserted at different depths within the lipid bilayer. Results: The activity of all compounds extends beyond membrane permeabilization, and the perturbation of membrane dynamics, often associated with the so-called \u201csand-in-a-gearbox\u201d mechanism, is a common feature among all systems analyzed. The membrane-active compounds induced a stiffening of the phospholipid bilayer by reducing lipid lateral mobility and decreasing water penetration, at least on the nanosecond timescale accessible to fluorescence measurements. Conclusions: The concentration range in which this behavior occurred was the same for all compounds studied. This threshold is, generally, higher than that required for membrane permeabilization and reflects near-complete coverage of the bilayer surface.<\/jats:p>","DOI":"10.3390\/antibiotics15080741","type":"journal-article","created":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T08:20:18Z","timestamp":1785486018000},"page":"741","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Bilayer Permeabilization and the \u2018Sand-in-a-Gearbox\u2019 Mechanism for Membrane-Active Molecules: Which Is Which?"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8292-3156","authenticated-orcid":false,"given":"Zahra","family":"Vaezi","sequence":"first","affiliation":[{"name":"Department of Chemical Sciences and Technologies, Tor Vergata University of Rome, Via della Ricerca Scientifica 1, 00133 Rome, Italy"},{"name":"Department of Biomaterial, Faculty of Interdisciplinary Science and Technologies, Tarbiat Modares University, Tehran 14115-154, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annalisa","family":"Bortolotti","sequence":"additional","affiliation":[{"name":"Department of Chemical Sciences and Technologies, Tor Vergata University of Rome, Via della Ricerca Scientifica 1, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristiano","family":"Di Stefano","sequence":"additional","affiliation":[{"name":"Department of Chemical Sciences and Technologies, Tor Vergata University of Rome, Via della Ricerca Scientifica 1, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simone","family":"Bonacorsi","sequence":"additional","affiliation":[{"name":"Department of Chemical Sciences and Technologies, Tor Vergata University of Rome, Via della Ricerca Scientifica 1, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3650-5628","authenticated-orcid":false,"given":"Valerio","family":"Santucci","sequence":"additional","affiliation":[{"name":"Department of Chemical Sciences and Technologies, Tor Vergata University of Rome, Via della Ricerca Scientifica 1, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federico","family":"Carneri","sequence":"additional","affiliation":[{"name":"Department of Chemical Sciences and Technologies, Tor Vergata University of Rome, Via della Ricerca Scientifica 1, 00133 Rome, Italy"},{"name":"Department of Chemistry, Biology and Biotechnology, Photoinduced Processes and Technologies Doctoral School, Perugia University, 06123 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Aisenbrey","sequence":"additional","affiliation":[{"name":"RMN et Biophysique des Membranes, Institut de Chimie de Strasbourg, UMR 7177, Universit\u00e9 de Strasbourg, 4, Rue Blaise Pascal, 67000 Strasbourg, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohini M.","family":"Konai","sequence":"additional","affiliation":[{"name":"Jawaharlal Nehru Centre for Advanced Scientific Research, Bengaluru 560064, India"},{"name":"Medicinal Chemistry and Biomaterial Laboratory (MCBL), Department of Chemical Sciences, Tezpur University, Napaam, Tezpur 784028, Assam, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yash","family":"Acharya","sequence":"additional","affiliation":[{"name":"Jawaharlal Nehru Centre for Advanced Scientific Research, Bengaluru 560064, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9364-7441","authenticated-orcid":false,"given":"Mariano","family":"Venanzi","sequence":"additional","affiliation":[{"name":"Department of Chemical Sciences and Technologies, Tor Vergata University of Rome, Via della Ricerca Scientifica 1, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0430-4602","authenticated-orcid":false,"given":"Roya","family":"Khosravi-Far","sequence":"additional","affiliation":[{"name":"InnoTech Precision Medicine, Boston, MA 02142, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5719-6073","authenticated-orcid":false,"given":"Burkhard","family":"Bechinger","sequence":"additional","affiliation":[{"name":"RMN et Biophysique des Membranes, Institut de Chimie de Strasbourg, UMR 7177, Universit\u00e9 de Strasbourg, 4, Rue Blaise Pascal, 67000 Strasbourg, France"},{"name":"Institut Universitaire de France, 75005 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jayanta","family":"Haldar","sequence":"additional","affiliation":[{"name":"Jawaharlal Nehru Centre for Advanced Scientific Research, Bengaluru 560064, 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University of Rome, Via della Ricerca Scientifica 1, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"eaau5480","DOI":"10.1126\/science.aau5480","article-title":"Antimicrobial Peptides: Application Informed by Evolution","volume":"368","author":"Lazzaro","year":"2020","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1007\/978-981-13-3588-4_11","article-title":"Selectivity of antimicrobial peptides: A complex interplay of multiple equilibria","volume":"1117","author":"Bobone","year":"2019","journal-title":"Adv. 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