title: Antifungal properties of peptidomimetics with an arginine-[β-(2,5,7-tri-tert-butylindol-3-yl)alanine]-arginine motif against Saccharomyces cerevisiae and Zygosaccharomyces bailii.
abstract: Due to increased occurrence of infections and food spoilage caused by yeast, there is an unmet need for new antifungal agents. The arginine-β-(2,5,7-tri-tert-butylindol-3-yl) alanine-arginine (R-Tbt-R) motif was previously proved useful in the design of an antifungal tripeptide. Here, an array of peptidomimetics based on this motif was investigated for antifungal and hemolytic activity. The five most promising modified tetrapeptide analogues ( 6: and 9-12: contain an additional C-terminal hydrophobic residue, and these were found to exhibit antifungal activity against Saccharomyces cerevisiae (MIC 6 and 12 μg mL(-1)) and Zygosaccharomyces bailii (MIC 6-25 μg mL(-1)). Four compounds ( 6: and 9-11: , had limited hemolytic activity (<10% hemolysis at 8 × MIC). Determination of their killing kinetics revealed that compound 9: displayed fungicidal effect. Testing against cells from an S. cerevisiae deletion mutant library indicated that interaction with yeast-specific fungal sphingolipids, most likely constitutes a crucial step in the mode of action. Interestingly, a lack of activity of peptidomimetics 6: and 9-11: towards Candida spp. was shown to be due to degradation or sequestering by the yeast. Due to their ultrashort nature, antifungal activity and low toxicity, the four compounds may have potential as leads for novel preservatives.
authors.affiliation: Department of Biology, Faculty of Science, University of Copenhagen, DK 2200 Copenhagen, Denmark.
authors.forename: Camilla Eggert
authors.initials: CE
authors.lastname: Larsen
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2100 Copenhagen, Denmark.
authors.forename: Camilla Josephine
authors.initials: CJ
authors.lastname: Larsen
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2100 Copenhagen, Denmark.
authors.forename: Henrik
authors.initials: H
authors.lastname: Franzyk
authors.affiliation: Department of Biology, Faculty of Science, University of Copenhagen, DK 2200 Copenhagen, Denmark bregenberg@bio.ku.dk.
authors.forename: Birgitte
authors.initials: B
authors.lastname: Regenberg
mesh_terms: D000935:Antifungal Agents / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D002175:Candida / Q000187:drug effects; D006461:Hemolysis / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability / Q000187:drug effects; D057786:Peptidomimetics / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D012441:Saccharomyces cerevisiae / Q000187:drug effects*; D020068:Zygosaccharomyces / Q000187:drug effects*
chemical_list: D000935:Antifungal Agents; D057786:Peptidomimetics
keywords: antimicrobial; fungicide; mannosyl di-(inositol phosphoryl) ceramide; mannosyl-inositol phosphorylceramide; spoilage