Fighting pathogenic yeasts with plant defensins and anti-fungal proteins from fungi

Abstract

Fungal infections represent a significant health risk worldwide. Opportunistic infections caused by yeasts, particularly by Candida spp. and their virulent emerging isolates, have become a major threat to humans, with an increase in fatal cases of infections attributed to the lack of effective anti-yeast therapies and the emergence of fungal resistance to the currently applied drugs. In this regard, the need for novel anti-fungal agents with modes of action different from those currently available is undeniable. Anti-microbial peptides (AMPs) are promising candidates for the development of novel anti-fungal biomolecules to be applied in clinic. A class of AMPs that is of particular interest is the small cysteine-rich proteins (CRPs). Among CRPs, plant defensins and anti-fungal proteins (AFPs) of fungal origin constitute two of the largest and most promising groups of CRPs showing anti-fungal properties, including activity against multi-resistant pathogenic yeasts. In this review, we update and compare the sequence, structure, and properties of plant defensins and AFPs with anti-yeast activity, along with their in vitro and in vivo potency. We focus on the current knowledge about their mechanism of action that may lead the way to new anti-fungals, as well as on the developments for their effective biotechnological production. KEY POINTS: • Plant defensins and fungal AFPs are alternative anti-yeast agents • Their multi-faceted mode of action makes occurrence of resistance rather improbable • Safe and cost-effective biofactories remain crucial for clinical application.

Keywords: Anti-fungal proteins (AFPs); Anti-yeast potency; Biotechnological production; Mode of action; Plant defensins.

Fig. 1

Sequence and structure of plant defensins and fungal AFPs. A Alignment of the sequence of the plant defensins NaD1 (UniProt ID: Q8GTM0), OsAFP1 (Q6K209), ZmD32 (B6SJE6), PsD1 (P81929), DmAMP1 (P0C8Y4), RsAFP2 (P30230), and Ppdef1 (van der Weerden et al. 2023). B Alignment of the sequence of the fungal AFPs PAF (B6HWK0), PeAfpA (A0A0A2K8K6), PAFB (D0EXD3), PAFC (B6HMF2), and NFAP2 (A0A1D0CRT2). In A and B, alignments were performed using the program Clustal Omega (https://www.ebi.ac.uk/Tools/msa/clustalo/); cysteines are shaded in black, conserved glycines in orange, basic amino acids in blue, and acid amino acids in red; the “asterisk” indicates identical amino acids, “colon” amino acids with strongly similar properties, and “full stop” amino acids with weakly similar properties; and γ-motifs are boxed in red. Ribbon representation of the structure of the plant defensin NaD1 (PDB ID: 1MR4) (C) and the anti-fungal proteins PAF (2MHV) (D) and PAFC (6TRM) (E). Cysteine disulfide bonds are shown in yellow, basic amino acids in blue, and acid amino acids in red. The location of the N-terminus, C-terminus, and the γ-motifs is indicated