title: Fungicidal activity of human lactoferrin-derived peptides based on the antimicrobial αβ region.
abstract: Owing to the increasing number of infections in hospitalised patients caused by resistant strains of fungi, there is a need to develop new therapeutic agents for these infections. Naturally occurring antimicrobial peptides may constitute models for developing such agents. A modified peptide sequence (CFQWKRAMRKVR; HLopt2) based on amino acid residues 20-31 of the N-terminal end of human lactoferrin (hLF) as well as a double-sized human lactoferricin-like peptide (amino acid residues 16-40; HLBD1) were investigated for their antifungal activities in vitro and in vivo. By in vitro assay, HLopt2 was fungicidal at concentrations of 12.5-25 μg/mL against Cryptococcus neoformans, Candida albicans, Candida krusei, Candida kefyr and Candida parapsilosis, but not against Candida glabrata. HLopt2 was demonstrated to have ≥ 16-fold greater killing activity than HLBD1. By inducing some helical formation caused by lactam bridges or by extending the assay time (from 2h to 20 h), HLBD1 became almost comparable with HLopt2 in its fungicidal activity. Killing of C. albicans yeast cells by HLopt2 was rapid and was accompanied by cytoplasmic and mitochondrial membrane permeabilisation as well as formation of deep pits on the yeast cell surface. In a murine C. albicans skin infection model, atopic treatment with the peptides resulted in significantly reduced yields of Candida from the infected skin areas. The antifungal activities of HLopt2 in vitro and in vivo suggest possible potential as a therapeutic agent against most Candida spp. and C. neoformans. The greatly improved antifungal effect of the lactam-modified HLBD1 indicates the importance of amphipathic helix formation for lethal activity.
authors.affiliation: Department of Infectious Diseases/Clinical Bacteriology, University of Gothenburg, Guldhedsgatan 10, S-413 46 Gothenburg, Sweden.
authors.forename: N
authors.initials: N
authors.lastname: Kondori
authors.forename: L
authors.initials: L
authors.lastname: Baltzer
authors.forename: G T
authors.initials: GT
authors.lastname: Dolphin
authors.forename: I
authors.initials: I
authors.lastname: Mattsby-Baltzer
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology*; D002175:Candida / Q000187:drug effects*; D002177:Candidiasis / Q000188:drug therapy; D003455:Cryptococcus neoformans / Q000187:drug effects*; D003881:Dermatomycoses / Q000188:drug therapy; D004195:Disease Models, Animal; D006801:Humans; D007781:Lactoferrin / Q000494:pharmacology*; D051379:Mice; D050296:Microbial Viability / Q000187:drug effects*; D016896:Treatment Outcome
chemical_list: D000890:Anti-Infective Agents; C490098:LTF protein, human; D007781:Lactoferrin