title: Antifungal activity in vitro and in vivo of a salmon protamine peptide and its derived cyclic peptide against Candida albicans.
abstract: Protamine peptide (PP) derived from salmon is a 14-mer with 10 arginine residues. We investigated the in vitro and in vivo antifungal activity of PP against Candida albicans PP showed a concentration-dependent dual mode of action, with fungicidal activity and inhibitory activity for hyphal development in vitro. At lethal concentrations of PP, intracellular accumulation of PP was energy-dependent but independent of endocytosis, and resulted in ATP efflux and the generation of reactive oxygen species in the cells. PP at sublethal concentrations inhibited hyphal development in C. albicans by binding to the cell surface. Though antifungal activity of PP was inactivated by high concentrations of NaCl, the antifungal activity of the synthetic cyclic (via a disulfide bond) form of PP (cyclic PP) was not. Cyclic PP also showed the concentration-dependent dual mode of action, and had five-fold greater antifungal activity than PP. The advantage of antifungal activity of cyclic PP compared with PP in vitro resulted in a high in vivo efficacy in a murine oral candidiasis model. Oral treatment with cyclic PP inhibited hyphal development of C. albicans on mouse tongues and protected against the development of severe candidiasis. This study shows the therapeutic potential of cyclic PP as an antifungal peptide against C. albicans.
authors.affiliation: Section of Infection Biology, Department of Functional Bioscience, Fukuoka Dental College, 2-15-1 Tamura, Sawara-ku, Fukuoka 814-0193, Japan.
authors.forename: Jun-Ichi
authors.initials: JI
authors.lastname: Nagao
authors.affiliation: Section of Infection Biology, Department of Functional Bioscience, Fukuoka Dental College, 2-15-1 Tamura, Sawara-ku, Fukuoka 814-0193, Japan chot1@college.fdcnet.ac.jp.
authors.forename: Tamaki
authors.initials: T
authors.lastname: Cho
authors.affiliation: Central Research Institute, Maruha Nichiro Corporation, 16-2, Wadai, Tsukuba-City, Ibaraki, 300-4295, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Mitarai
authors.affiliation: Central Research Institute, Maruha Nichiro Corporation, 16-2, Wadai, Tsukuba-City, Ibaraki, 300-4295, Japan.
authors.forename: Keishi
authors.initials: K
authors.lastname: Iohara
authors.affiliation: Teikyo University institute of Medical Mycology, 3590 Otsuka, Hachioji, Tokyo, 192-0395, Japan.
authors.forename: Kazumi
authors.initials: K
authors.lastname: Hayama
authors.affiliation: Teikyo University institute of Medical Mycology, 3590 Otsuka, Hachioji, Tokyo, 192-0395, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Abe
authors.affiliation: Section of Infection Biology, Department of Functional Bioscience, Fukuoka Dental College, 2-15-1 Tamura, Sawara-ku, Fukuoka 814-0193, Japan.
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Tanaka
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000935:Antifungal Agents / Q000378:metabolism* / Q000627:therapeutic use; D002176:Candida albicans / Q000187:drug effects* / Q000254:growth & development / Q000502:physiology; D002180:Candidiasis, Oral / Q000188:drug therapy; D004195:Disease Models, Animal; D006494:Heparin Antagonists / Q000378:metabolism* / Q000627:therapeutic use; D025301:Hyphae / Q000187:drug effects / Q000254:growth & development; D051379:Mice; D050296:Microbial Viability / Q000187:drug effects; D010456:Peptides, Cyclic / Q000378:metabolism* / Q000627:therapeutic use; D011479:Protamines / Q000378:metabolism* / Q000627:therapeutic use; D017382:Reactive Oxygen Species / Q000378:metabolism; D012474:Salmon; D016896:Treatment Outcome
chemical_list: D000935:Antifungal Agents; D006494:Heparin Antagonists; D010456:Peptides, Cyclic; D011479:Protamines; D017382:Reactive Oxygen Species; D000255:Adenosine Triphosphate
keywords: Candida albicans; antifungal peptide; oral candidiasis