Abstract
The peptidomimetic LTX109 (arginine-tertbutyl tryptophan-arginine-phenylethan) was previously shown to have antibacterial properties. Here, we investigated the activity of this novel antimicrobial peptidomimetic on the yeast Saccharomyces cerevisiae. We found that LTX109 was an efficient fungicide that killed all viable cells in an exponentially growing population as well as a large proportion of cells in biofilm formed on an abiotic surface. LTX109 had similar killing kinetics to the membrane-permeabilizing fungicide amphotericin B, which led us to investigate the ability of LTX109 to disrupt plasma membrane integrity. S. cerevisiae cells exposed to a high concentration of LTX109 showed rapid release of potassium and amino acids, suggesting that LTX109 acted by destabilizing the plasma membrane. This was supported by the finding that cells were permeable to the fluorescent nucleic acid stain SYTOX Green after a few minutes of LTX109 treatment. We screened a haploid S. cerevisiae gene deletion library for mutants resistant to LTX109 to uncover potential molecular targets. Eight genes conferred LTX109 resistance when deleted and six were involved in the sphingolipid biosynthetic pathway (SUR1, SUR2, SKN1, IPT1, FEN1 and ORM2). The involvement of all of these genes in the biosynthetic pathway for the fungal-specific lipids mannosylinositol phosphorylceramide (MIPC) and mannosyl di-(inositol phosphoryl) ceramide (M(IP)2C) suggested that these lipids were essential for LTX109 sensitivity. Our observations are consistent with a model in which LTX109 kills S. cerevisiae by nonspecific destabilization of the plasma membrane through direct or indirect interaction with the sphingolipids.
Highlights
Infections caused by pathogenic yeast such as Candida spp. affect a large number of immunosuppressed patients and are an increasing medical problem [1,2]
This study demonstrated the fungicidal activity of the peptidomimetic LTX109
Antimicrobial peptidomimetics are peptide-like compounds, of which most are bactericides [49,50,51,52,53]
Summary
Infections caused by pathogenic yeast such as Candida spp. affect a large number of immunosuppressed patients and are an increasing medical problem [1,2]. Fungal infections are currently treated with one of four major classes of antifungals. Decreased susceptibility to the most frequently used antifungal, fluconazole, has recently been reported, and the number of nonsusceptible C. glabrata isolates from humans is increasing [8,9]. An additional complication in the treatment of nosocomial fungal infections is the frequent formation by fungi of sessile communities called biofilms in association with medical implants [13]. Most systemic antifungals are fungistatic against yeasts, so they are primarily effective against actively growing cells and have poor activity against cells in biofilms
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