The Synthetic Amphipathic Peptidomimetic LTX109 Is a Potent Fungicide That Disturbs Plasma Membrane Integrity in a Sphingolipid Dependent Manner
作者： Rasmus Bojsen , Rasmus Torbensen , Camilla Eggert Larsen , Anders Folkesson , Birgitte Regenberg
DOI: 10.1371/JOURNAL.PONE.0069483
关键词: Sphingolipid 、 Ceramide 、 Biochemistry 、 Amino acid 、 Saccharomyces cerevisiae 、 Peptidomimetic 、 Cell membrane 、 Mutant 、 Biology 、 Population 、 General Biochemistry, Genetics and Molecular Biology 、 General Agricultural and Biological Sciences 、 General Medicine
摘要: The peptidomimetic LTX109 (arginine-tertbutyl tryptophan-arginine-phenylethan) was previously shown to have antibacterial properties. Here, we investigated the activity of this novel antimicrobial on yeast Saccharomyces cerevisiae. We found that an efficient fungicide killed all viable cells in exponentially growing population as well a large proportion biofilm formed abiotic surface. had similar killing kinetics membrane-permeabilizing amphotericin B, which led us investigate ability disrupt plasma membrane integrity. S. cerevisiae exposed high concentration showed rapid release potassium and amino acids, suggesting acted by destabilizing membrane. This supported finding were permeable fluorescent nucleic acid stain SYTOX Green after few minutes treatment. screened haploid gene deletion library for mutants resistant uncover potential molecular targets. Eight genes conferred resistance when deleted six involved sphingolipid biosynthetic pathway (SUR1, SUR2, SKN1, IPT1, FEN1 ORM2). involvement these fungal-specific lipids mannosylinositol phosphorylceramide (MIPC) mannosyl di-(inositol phosphoryl) ceramide (M(IP)2C) suggested essential sensitivity. Our observations are consistent with model kills nonspecific destabilization through direct or indirect interaction sphingolipids.
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