title: Marine sponge cyclic peptide theonellamide A disrupts lipid bilayer integrity without forming distinct membrane pores.
abstract: Theonellamides (TNMs) are antifungal and cytotoxic bicyclic dodecapeptides derived from the marine sponge Theonella sp. These peptides specifically bind to 3β-hydroxysterols, resulting in 1,3-β-D-glucan overproduction and membrane damage in yeasts. The inclusion of cholesterol or ergosterol in phosphatidylcholine membranes significantly enhanced the membrane affinity of theonellamide A (TNM-A) because of its direct interaction with 3β-hydroxyl groups of sterols. To better understand TNM-induced membrane alterations, we investigated the effects of TNM-A on liposome morphology. (31)P nuclear magnetic resonance (NMR) and dynamic light scattering (DLS) measurements revealed that the premixing of TNM-A with lipids induced smaller vesicle formation. When giant unilamellar vesicles were incubated with exogenously added TNM-A, confocal micrographs showed dynamic changes in membrane morphology, which were more frequently observed in cholesterol-containing than sterol-free liposomes. In conjunction with our previous data, these results suggest that the membrane action of TNM-A proceeds in two steps: 1) TNM-A binds to the membrane surface through direct interaction with sterols and 2) accumulated TNM-A modifies the local membrane curvature in a concentration-dependent manner, resulting in dramatic membrane morphological changes and membrane disruption.
authors.affiliation: Department of Chemistry, Graduate School of Science, Osaka University, Osaka 560-0043, Japan.
authors.forename: Rafael Atillo
authors.initials: RA
authors.lastname: Espiritu
authors.affiliation: Department of Chemistry, Graduate School of Science, Osaka University, Osaka 560-0043, Japan; JST ERATO, Lipid Active Structure Project, Osaka 560-0043, Japan.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Cornelio
authors.affiliation: JST ERATO, Lipid Active Structure Project, Osaka 560-0043, Japan.
authors.forename: Masanao
authors.initials: M
authors.lastname: Kinoshita
authors.affiliation: Department of Chemistry, Graduate School of Science, Osaka University, Osaka 560-0043, Japan. Electronic address: matsmori@chem.kyushu-univ.jp.
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Matsumori
authors.affiliation: Department of Chemistry, Graduate School of Science, Osaka University, Osaka 560-0043, Japan; JST ERATO, Lipid Active Structure Project, Osaka 560-0043, Japan.
authors.forename: Michio
authors.initials: M
authors.lastname: Murata
authors.affiliation: Division of Bioinformatics and Chemical Genomics, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Nishimura
authors.affiliation: Division of Bioinformatics and Chemical Genomics, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Kakeya
authors.affiliation: Chemical Genomics Research Group, RIKEN Center for Sustainable Resource Science, Saitama 351-0198, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Yoshida
authors.affiliation: Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Matsunaga
mesh_terms: D000818:Animals; D008051:Lipid Bilayers / Q000737:chemistry*; D008386:Marine Biology; D010456:Peptides, Cyclic / Q000737:chemistry*; D010743:Phospholipids / Q000737:chemistry; D011161:Porifera / Q000737:chemistry*
chemical_list: D008051:Lipid Bilayers; D010456:Peptides, Cyclic; D010743:Phospholipids; C581283:theonellamide A
keywords: Confocal microscopy; Liposomes; Mechanism of action; Solid state nuclear magnetic resonance; Theonellamide A