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    • Plant defensins Vriens et al and linear AMPs Domingues et

    2024-02-29

    Plant defensins (Vriens et al., 2014) and linear AMPs (Domingues et al., 2015, Liu et al., 2008) have been shown to present several modes of action. Among these different mechanisms, permeabilization of the fungal membrane has been described as a secondary effect of plant defensin action (Vriens et al., 2014), but is primarily involved in the antimicrobial activity of linear peptides (Bechinger and Lohner, 2006). Like native plant defensins, such as NaD1 (Van Der Weerden et al., 2010) or linear antimicrobial peptides (Van Der Weerden et al., 2010), KT43C causes fungal membrane permeabilization of F. culmorum at the MIC (Fig. 5), but at a slower rate of action than the native peptide (data not shown). The time difference can be explained by the formation of oligomers of the synthetic peptide or the necessity to reach a sufficient concentration of peptide at the surface of fungal membrane (Thevissen et al., 2004). Another hypothesis would be a limited mobility of SM-164 of KT43C that tend to form into the bilayer environment because of changes in hydrophobicity, as described for tachyplesin (Han and Lee, 2015). At high concentrations, KT43C induces a high production of ROS in Fusarium hyphae (Fig. 6). The generation of ROS is involved in mechanisms related to oxidative stress and damage, leading generally to cell-death. The interaction with intracellular targets and the overproduction of ROS in the fungal cytoplasm has been highlighted for several defensins (Vriens et al., 2014) and linear AMPs (Huang et al., 2010). In addition, a model, involving pore-formation and intracellular target strategy, has already been considered for several linear AMPs (Mason et al., 2007). Like KT43C, ROS production with NaD1 was only observed at concentrations greater than the MIC, even when membrane permeabilization was observed, suggesting a partial role for oxidative stress in fungal inhibition (Hayes et al., 2013). A major issue with the use of cAMPs in pharmaceuticals or food applications is their potential toxicity towards mammalian cells. The reduction of hydrophobicity and the absence of disulfide bridges in linear derivatives have been pointed out as key elements in reducing their cytotoxicity (Liu et al., 2008). KT43C did not induce red blood cells lysis in the range of concentration used for the antifungal assays. Due to the presence of cholesterol, mammalian cell membranes have been shown to be less sensitive to destabilization by linear cationic AMPs than fungal membranes (containing mostly ergosterol) (Mason et al., 2007). Another study from our group has shown that the synthetic cationic peptide OOWW-NH2 is inactive against gut Caco-2 cell lines (Thery et al., 2018). The cytotoxicity of plant defensins has already been proven to be low, even negligible (Thevissen et al., 2004). In addition, Liu et al. (2008) showed that a linear analogue of hBD-3 displayed lower cytotoxicity compared to the native form of HBD-3. The decreased cytotoxicity towards mammalian cells of linear derivatives of AMPs and defensins has been attributed to the removal of the disulfide bridges, decreasing the overall hydrophobicity (Liu et al., 2008). KT43C (20 μg.ml−1) was used as an ingredient in the preparation of chilled dough and delayed the growth of F. culmorum by 2 days in a challenge test. The use of natural (Lucera et al., 2012, Rai et al., 2016, Rydlo et al., 2006) and synthetic (Appendini and Hotchkiss, 2000, Thery et al., 2018) AMPs to prevent spoilage of food products has been reported. Thus, the synthetic analogue of the human β-defensin 3 protects bread against environmental contaminants, with a shelf-life extension of 3 days (Thery et al., 2016). Although the concentration of KT43C used in this test was the MIC against F. culmorum, the conidial germination was not completely inhibited. The presence of other dough ingredients and proteases resulting from the preparation process may affect the antifungal action of the peptide. The sensitivity of AMPs to proteolytic digestion is a major concern for a potential use as food additive to avoid further action once in the intestinal system.