{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T16:16:03Z","timestamp":1789229763166,"version":"build-2803163510"},"reference-count":69,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2024,7,4]],"date-time":"2024-07-04T00:00:00Z","timestamp":1720051200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Servicio para el Control de la Esterilizaci\u00f3n (SCE)\/Laboratorio de Microbiolog\u00eda Oral (LMO) of the University of Oviedo","award":["FUO-19-258"],"award-info":[{"award-number":["FUO-19-258"]}]},{"name":"Servicio para el Control de la Esterilizaci\u00f3n (SCE)\/Laboratorio de Microbiolog\u00eda Oral (LMO) of the University of Oviedo","award":["FUO-21-304"],"award-info":[{"award-number":["FUO-21-304"]}]},{"name":"Servicio para el Control de la Esterilizaci\u00f3n (SCE)\/Laboratorio de Microbiolog\u00eda Oral (LMO) of the University of Oviedo","award":["SV-03-FSCARRASCO"],"award-info":[{"award-number":["SV-03-FSCARRASCO"]}]},{"name":"Fundaci\u00f3n Sira Carrasco para la Ayuda a la Fibrosis Qu\u00edstica","award":["FUO-19-258"],"award-info":[{"award-number":["FUO-19-258"]}]},{"name":"Fundaci\u00f3n Sira Carrasco para la Ayuda a la Fibrosis Qu\u00edstica","award":["FUO-21-304"],"award-info":[{"award-number":["FUO-21-304"]}]},{"name":"Fundaci\u00f3n Sira Carrasco para la Ayuda a la Fibrosis Qu\u00edstica","award":["SV-03-FSCARRASCO"],"award-info":[{"award-number":["SV-03-FSCARRASCO"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Human defensins are cysteine-rich peptides (Cys-rich peptides) of the innate immune system. Defensins contain an ancestral structural motif (i.e., \u03b3-core motif) associated with the antimicrobial activity of natural Cys-rich peptides. In this study, low concentrations of human \u03b1- and \u03b2-defensins showed microbicidal activity that was not associated with cell membrane permeabilization. The cell death pathway was similar to that previously described for human lactoferrin, also an immunoprotein containing a \u03b3-core motif. The common features were (1) cell death not related to plasma membrane (PM) disruption, (2) the inhibition of microbicidal activity via extracellular potassium, (3) the influence of cellular respiration on microbicidal activity, and (4) the influence of intracellular pH on bactericidal activity. In addition, in yeast, we also observed (1) partial K+-efflux mediated via Tok1p K+-channels, (2) the essential role of mitochondrial ATP synthase in cell death, (3) the increment of intracellular ATP, (4) plasma membrane depolarization, and (5) the inhibition of external acidification mediated via PM Pma1p H+-ATPase. Similar features were also observed with BM2, an antifungal peptide that inhibits Pma1p H+-ATPase, showing that the above coincident characteristics were a consequence of PM H+-ATPase inhibition. These findings suggest, for the first time, that human defensins inhibit PM H+-ATPases at physiological concentrations, and that the subsequent cytosolic acidification is responsible for the in vitro microbicidal activity. This mechanism of action is shared with human lactoferrin and probably other antimicrobial peptides containing \u03b3-core motifs.<\/jats:p>","DOI":"10.3390\/ijms25137335","type":"journal-article","created":{"date-parts":[[2024,7,4]],"date-time":"2024-07-04T06:28:54Z","timestamp":1720074534000},"page":"7335","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["The Antimicrobial Activity of Human Defensins at Physiological Non-Permeabilizing Concentrations Is Caused by the Inhibition of the Plasma Membrane H+-ATPases"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7827-981X","authenticated-orcid":false,"given":"Mar\u00eda T.","family":"Andr\u00e9s","sequence":"first","affiliation":[{"name":"Laboratory of Oral Microbiology (LMO), University Clinic of Dentistry (CLUO), University of Oviedo, 33006 Oviedo, Asturias, Spain"},{"name":"Health Research Institute of the Principality of Asturias (ISPA), 33011 Oviedo, Spain"},{"name":"SamerLabs SL, Asturias Technology Park, 33428 Llanera, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia","family":"Fierro","sequence":"additional","affiliation":[{"name":"Laboratory of Oral Microbiology (LMO), University Clinic of Dentistry (CLUO), University of Oviedo, 33006 Oviedo, Asturias, Spain"},{"name":"Primary Care Emergency Service, Cantabrian Health Service, 39000 Santander, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria","family":"Antu\u00f1a","sequence":"additional","affiliation":[{"name":"Laboratory of Oral Microbiology (LMO), University Clinic of Dentistry (CLUO), University of Oviedo, 33006 Oviedo, Asturias, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2752-0690","authenticated-orcid":false,"given":"Jos\u00e9 F.","family":"Fierro","sequence":"additional","affiliation":[{"name":"Laboratory of Oral Microbiology (LMO), University Clinic of Dentistry (CLUO), University of Oviedo, 33006 Oviedo, Asturias, Spain"},{"name":"Health Research Institute of the Principality of Asturias (ISPA), 33011 Oviedo, Spain"},{"name":"Deparment of Functional Biology (Microbiology), Faculty of Medicine, University of Oviedo, 33006 Oviedo, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,7,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1038\/ni1206","article-title":"Mammalian defensins in the antimicrobial immune response","volume":"6","author":"Selsted","year":"2005","journal-title":"Nat. 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