Antifungal Plant Defensins as an Alternative Tool to Combat Candidiasis

Abstract

Currently, the spread of fungal infections is becoming an urgent problem. Fungi of the Candida genus are opportunistic microorganisms that cause superficial and life-threatening systemic candidiasis in immunocompromised patients. The list of antifungal drugs for the treatment of candidiasis is very limited, while the prevalence of resistant strains is growing rapidly. Therefore, the search for new antimycotics, including those exhibiting immunomodulatory properties, is of great importance. Plenty of natural compounds with antifungal activities may be extremely useful in solving this problem. This review evaluates the features of natural antimicrobial peptides, namely plant defensins as possible prototypes of new anticandidal agents. Plant defensins are important components of the innate immune system, which provides the first line of defense against pathogens. The introduction presents a brief summary regarding pathogenic Candida species, the pathogenesis of candidiasis, and the mechanisms of antimycotic resistance. Then, the structural features of plant defensins, their anticandidal activities, their mechanisms of action on yeast-like fungi, their ability to prevent adhesion and biofilm formation, and their combined action with conventional antimycotics are described. The possible mechanisms of fungal resistance to plant defensins, their cytotoxic activity, and their effectiveness in in vivo experiments are also discussed. In addition, for the first time for plant defensins, knowledge about their immunomodulatory effects is also presented.

Keywords: Candida albicans; Candida auris; antibiofilm activity; anticandidal activity; antifungal drugs; candidiasis; drug resistance; fungi; immunomodulatory effects; plant defensins; prevention of fungus adhesion.

Figure 1

Amino acid sequences of plant defensins and their synthetic analogs possessing activity against fungi of the Candida genus. The amino acid sequences of the following peptides are given in: γ33-41PvD1++ and γ31-45PvD1++ [35]; HsLin06_18 [36]; OsAFP1 [37]; CaCDef-like [38]; Lp-Def1 [39]; NbD6 [40]; Ppdef1 [41]; Javanicin [42]; ♦ A₄₂,₄₄R₃₇,₃₈W_36,39γ_32–46VuDef(WR) [43]. Art v 1 structure, the defensin-like allergen of mugwort pollen, is also present for comparation. Cysteine residues are red, conservative amino acids are blue, and homologous amino acids are bold. Amino acids included in the IgE-binding epitopes [44] and the dominant T-cell epitope [45] of Art v 1 are highlighted in green and gray, respectively. X—α-aminobutyric acid. *—unknown amino acid. The molecular weight (Mw) and isoelectric point (pI) of peptides are also presented.

Figure 2

Structural organization of plant defensin NaD1 from flowers of ornamental tobacco (PDB 1MR4) [46] and human β-defensin HBD2 (PDB 1FD4) [47]. α-Helices and β-sheets are colored red and blue, respectively. The formation of disulfide bonds in the structures of defensins is also shown.

Figure 3

Possible immunomodulatory effects of plant defensins in low concentrations without and upon infection. (A) Plant defensins have a mainly pro-inflammatory effect on the epithelium, increasing the production of AMPs and pro-inflammatory cytokines/chemokines, as well as the abundance of PRRs and activity of the transcription factors of inflammatory response. (B) Under infection, plant defensins have a similar pro-inflammatory effect on the epithelium and also reduce the internalization of the pathogen. (C) Plant defensins are able to penetrate the epithelial barrier and affect various types of immune cells, increasing the production of pro- and anti-inflammatory cytokines/chemokines and growth factors. Plant defensins also affect endothelial cells interfering with the VEGF pathway. (D) Under infection, plant defensins affect epithelial–immune cell crosstalk, leveling the stimulating or, conversely, inhibitory effects of the pathogenic fungus and thereby remodulating the immune response. moDC—monocyte-derived dendritic cell, Treg—regulatory CD4⁺ FoxP3⁺ T cell; E2F-1, EGR, CBF, AP-1, etc.,—transcriptional factors of inflammatory response; TLR2—cell-membrane-associated receptor; HBD—human β-defensin; VEGF—vascular endothelial growth factor; IL-1β, IL-6, IL-8/CXCL8, IL-10, IL-12, IL-17, IL-27, IP-10, TNFα, and GM-CSF—pro- and anti-inflammatory cytokines, chemokines, and growth factors. Blue and red arrows indicate the upregulation/downregulation of genes encoding the corresponding proteins or an increase/decrease in the abundance of the appropriate proteins or an inhibitory/activating effect of plant defensins on some processes.