title: The peculiar N- and (-termini of trichogin GA IV are needed for  membrane interaction and human cell death induction at doses lacking  antibiotic activity.
abstract: Peptaibiotics, non-ribosomally synthetized peptides from various ascomycetes, are uniquely characterized by dialkylated a-amino acids, a rigid heli cal conformation, and membrane permeation properties. Although generally considered as antimicrobial peptides, peptaibiotics may display other toxicological properties, and their function is in many cases unknown. With the goal to define the biological activity and selectivity of the peptaibiotictrichogin GA IV from the human opportunist Trichodenna longibrachiatum we analyzed its membrane interaction,cytotoxic activity and antibacterial effect. Trichogin GA IV effectively killed several types of healthy and neoplastic human cells at doses (EC 50%= 4-6 ~) lacking antibiotic effects on both Gram- and Gram+ bacteria(MIC > 64 ~ ). The peptaibiotic distinctive (-terminal primary alcohol was found to cooperate with theN-terminal n-octanoyl group to permeate the membrane phospholipid bilayer and to mediate effective binding and active endocytosis of trichogin GA IV in eukaryotic cells, two steps essential for cell death induction.Replacement of one Gly with Lys plus the simultaneous esterification of the (-terminus, strongly increased trichogin GA IV anti-Gram+ activity (MIC 1-4 ~ ). but further mitigated its cytotoxicity on human cells.
authors.forename: Regina
authors.initials: R
authors.lastname: Tavano
authors.forename: Giulia
authors.initials: G
authors.lastname: Malachin
authors.forename: Marta
authors.initials: M
authors.lastname: De Zotti
authors.forename: Cristina
authors.initials: C
authors.lastname: Peggion
authors.forename: Barbara
authors.initials: B
authors.lastname: Biondi
authors.forename: Fernando
authors.initials: F
authors.lastname: Forrnaggio
authors.forename: Emanuele
authors.initials: E
authors.lastname: Papini
mesh_terms: D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001667:Binding, Competitive; D002460:Cell Line; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism; D002463:Cell Membrane Permeability / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002784:Cholesterol / Q000737:chemistry / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004705:Endocytosis; D018922:HL-60 Cells; D006367:HeLa Cells; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D055666:Lipopeptides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D008563:Membrane Lipids / Q000737:chemistry* / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D018613:Microscopy, Confocal; D010713:Phosphatidylcholines / Q000737:chemistry / Q000378:metabolism; D010714:Phosphatidylethanolamines / Q000737:chemistry / Q000378:metabolism; D010715:Phosphatidylglycerols / Q000737:chemistry / Q000378:metabolism; D053835:Unilamellar Liposomes / Q000737:chemistry* / Q000378:metabolism
chemical_list: C410262:1,2-dioleoyl-glycero-3-phosphatidyl ethanolamine; D000900:Anti-Bacterial Agents; D055666:Lipopeptides; D008563:Membrane Lipids; D010713:Phosphatidylcholines; D010714:Phosphatidylethanolamines; D010715:Phosphatidylglycerols; D053835:Unilamellar Liposomes; C116419:trichogin GA IV; C051388:1,2-dioleoyl-sn-glycero-3-phosphoglycerol; D002784:Cholesterol; C017251:1,2-oleoylphosphatidylcholine