A synthetic peptide mimic killsCandida albicansand synergistically prevents infection

Abstract

More than two million people worldwide are affected by life-threatening, invasive fungal infections annually.Candidaspecies are the most common cause of nosocomical, invasive fungal infections and are associated with mortality rates above 40%. Despite the increasing incidence of drug-resistance, the development of novel antifungal formulations has been limited. Here we investigate the antifungal mode of action and therapeutic potential of positively charged, synthetic peptide mimics to combat infections byCandida albicans. These synthetic polymers cause stress to the endoplasmic reticulum and affect protein glycosylation, a distinct mode of action compared to currently approved antifungal drugs. The most promising polymer composition caused damage to the mannan layer of the cell wall, with additional membrane-disrupting activity. The synergistic combination of the polymer with caspofungin prevented infection of human epithelial cells in vitro, improved fungal clearance by human macrophages, and significantly increased host survival in aGalleria mellonellamodel of systemic candidiasis. Additionally, prolonged exposure ofC. albicansto the synergistic combination of polymer and caspofungin did not lead to the evolution of resistant strains in vitro. Together, this work highlights the enormous potential of these synthetic peptide mimics to be used as novel antifungal formulations as well as adjunctive antifungal therapy.

Mimicking Charged Host-Defense Peptides to Tune the Antifungal Activity and Biocompatibility of Amphiphilic Polymers

“…This has also been demonstrated previously for PA-50:25:25. 67 The increased tolerance of the caspofungin-resistant C. glabrata isolate to our polymers indicates a potentially overlapping antifungal mechanism. However, the synergy experiment (Figure 6) suggests different modes of action because synergy with caspofungin was observed in combination with the polymers.…”

“…22 We have also shown PA-50:25:25 to be active against drug-resistant or -tolerant clinical C. albicans isolates. 67 Polymer Gu-45:25:30 showed comparable MICs to treatment with PA-50:25:25 for all tested fungal isolates except for the C. glabrata clinical isolate which was susceptible at lower concentrations considering both MIC 90% (64−128 vs >512 μg/ mL, Table 7) and MIC 50% (32−64 vs 128 μg/mL, Table S7). Similarly, the polymers Im-75:10: Overall, the ternary polymers remained active against clinical isolates and lab strains of Candida spp.…”

“…This behavior has been previously reported for PA-50:25:25. 67 To assess whether the observed biological synergy could be due to molecular interactions between the polymers and the antifungal drugs caspofungin and fluconazole, we performed diffusion-ordered NMR spectroscopy (DOSY) with PA/Im/ Gu (composed of all three investigated charged groups) and the antifungal drugs (Table 6 and Figures S26−S31). Combinations of PA/Im/Gu with AmpB had solubility issues at the required concentrations and were not further analyzed.…”

“…67 Overall, our results demonstrate the potential of polyacrylamides with various charged groups as antifungal compounds in synergistic combinations with other approved antifungal drugs to increase efficiency and potentially decrease the emergence of drug resistance, as demonstrated for PA-50:25:25. 67 Activity against Clinical Isolates of Candida Species and C. neoformans. In addition to C. albicans, other commonly detected strains in candidaemia patients include C. glabrata (now: Nakaseomyces glabrata), C. parapsilosis, Candida tropicalis, Candida krusei (now: Pichia kudriavzevii), and Candida dubliniensis.…”

“…The mode of action studies and activity of PA-50:25:25 against caspofungin-resistant strains in a previous study further supports different targets of caspofungin and the synthetic polymer. 67 Gu displayed the most promising potential as antifungal lead compounds.…”