Combination of metals and enzymes as effective antifungal agents is currently being conducted due to the growing antifungal resistance problem. Metals are attracting special attention due to the wide variety of ligands that can be used for them, including chemically synthesized and naturally obtained variants as a result of the so-called “green synthesis”. The main mechanism of the antifungal action of metals is the triggering of the generation and accumulation of reactive oxygen species (ROS). Further action of ROS on various biomolecules is nonspecific. Various hydrolytic enzymes exhibit antifungal properties by affecting the structural elements of fungal cells (cell walls, membranes), fungal quorum sensing molecules, fungal own protective agents (mycotoxins and antibiotics), and proteins responsible for the adhesion and formation of stable, highly concentrated populations in the form of biofilms.
1. Introduction
The accumulation of information about the role that microscopic fungi can play in the development of a number of negative processes affecting human health
[1][2][3] has led to increasing interest in antifungals that can control and reduce the growth, as well as the metabolic activity, of these biological objects, especially those associated with pathogens
[4]. The seriousness of these tasks is increasing due to the fact that in some cases, fungal cells may develop resistance to the chemical formulations used against them
[5][6][7].
A number of current scientific studies are related to the development of effective antifungals
[8]. Among the new trends in the development of effective antifungals, the prospects of a possible combination of various chemical compounds
[7] with different mechanisms of action on fungal cells are being considered. This approach can enable researchers to overcome the development of adaptive processes in fungi and, possibly, reduce the doses of the substances used, increasing the effectiveness of their action in such combinations. When implementing such a combined approach to suppressing the growth and metabolic activity of fungi, the main question arises about what is better to combine with what, and what may be unpromising. One of the possible answers to this question is based on the use of metal nanomaterials such as metal-nanoparticles, metal-organic frameworks, etc., to which no resistance is formed by most microorganisms since the mechanism of suppression of biological processes is primarily associated with the generation of reactive oxygen species (ROS) in the cells. Metals such as Ag, Cu, Fe, Zn, Se, Ni, Au, Zr, Ce, Ti, and Pd have been studied in regard to compounds possessing antifungal activity
[9][10][11][12]. At the same time, current scientific research on the antifungal properties of metals is mainly focused on the study of Ag and Au nanoparticles (NPs)
[10][11][12][13][14][15] since the antimicrobial effectiveness of their action has been known for a long time.
Among the various organic synthetic ligands for the metals used in research in this direction, the so-called “green synthesized” metal-containing NPs should be noted. These “green synthesized” metal-containing NPs are formed inside the cells of microorganisms (bacteria, fungus, yeast) in vivo or using plant extracts, polysaccharides of phototrophic microorganisms, and extracellular enzymes of mycelial fungi
[10][14][15][16][17]. “Green synthesis” is an environmentally friendly synthesis technique that avoids the formation of undesired by-products and costs less. Moreover, it was found that “green synthesis” makes it possible to obtain NPs with identical antifungal properties compared to similar chemically synthesized metal-containing compounds that are, in some cases, superior to them
[17].
It is known that the combination of metal NPs with known chemical fungicides makes it possible to reduce the minimum inhibitory concentration (MIC) of the latter by more than eight times
[17]. However, despite this researchers decided to consider the possibility of combining metal-containing compounds with biological molecules having catalytic properties, in particular, with various enzymes exhibiting antifungal activity instead of chemically synthesized fungicides. It has been previously shown that the efficiency of the use of metal NPs can be increased by combining them with cyclic peptides that exhibit antifungal properties
[18]. Unlike peptides that exhibit antimicrobial activity, the enzymes have catalytic activity
[19], which allows them not just to trigger destructive processes against fungi but to repeatedly participate in these acts of biocatalysis, deepening antifungal processes. In addition, a wide substrate range of action of the enzymes themselves allows us to consider the possibility of not only their destructive activity against fungal cells but also against the most important fungal molecules involved in the formation of their quorum sensing (QS) and adhesion
[20] and molecules that ensure their own safety (antibiotics
[21] and mycotoxins
[22]).
2. Antifungal Agents Based on Metal Nanoparticles, Metal–Organic Frameworks and Their Composites
Multiple antifungal agents have been developed to date on the basis of metal nanoparticles (NPs) and/or metal–organic frameworks (MOFs) (
Table 1,
[11][12][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37],
Figure 1).
Figure 1. Some representative metal NPs and MOFs with antifungal activities. Crystal structures of Ag (1741252), ZnO (13950), Fe3O4 (1612598), HKUST-1 (2091261), MIL-53-Fe (2088536), and UiO-66 (2054314) were obtained from CCDC, then expanded in Mercury (v.4.2.0, CCDC, Cambridge, UK) and visualized in PyMOL (v.1.7.6, Schrödinger Inc., New York, NY, USA). Water-accessible molecular surface is indicated by light grey while atoms are colored by element: Ag–grey, Zn–slate, O–red, Fe–orange, C–deep blue, H–white, Zr–cyan.
Table 1. Antifungals based on metal nanoparticles (NPs), metal–organic frameworks (MOFs), and their composites *.
Antifungal Agent [Reference] |
Target of Action |
Antifungal Activity |
Efficiency of Antifungal Action |
ZrO2-Ag2O (14–42 nm) [23] |
Candida albicans, C. dubliniensis, C. glabrata, C. tropicalis |
The growth rate inhibition |
89–97% inhibition |
WS2/ZnO nano-hybrids [24] |
C. albicans |
Inhibition of biofilm formation |
91% inhibition |
CuO@C (36–123 nm) [25] |
Alternaria alternata, Fusarium oxysporum, Penicillium digitatum, Rhizopus oryzae |
Inhibition of the hydrolytic activity of fungal enzymes used by them for their own metabolism |
Inhibition (100 μg/mL) of cellulases and amylases secreted by fungi: 38% and 42% for A. alternata, 39% and 45% for F. oxysporum, 24% and 67% for P. digitatum, and 20% and 24%for R. oryzae, respectively |
ZnO NPs [26] |
C. albicans, Aspergillus niger |
Inhibition of growth |
Large enough zone of growth absence (8-9 mm) |
ZnO NPs (20–45 nm) [27] |
Erythricium salmonicolor |
Notable thinning of the hyphae and cell walls, liquefaction of the cytoplasmic content with decrease in presence of a number of vacuoles |
Significant inhibition (9–12 mmol/L) of cell growth |
ZnO–TiO2 NPs (8–33 nm) [28] |
A. flavus |
High level of ROS production and oxidative stress induction. Treated objects have a lower count of spores and damaged tubular filaments and noticeably thinner hyphae compared to the untreated fungi |
Fungicidal inhibition (150 μg/mL) zone is 100 % |
ZnO NPs (40–50 nm) [29] |
C. albicans |
High level of ROS production |
MIC = 32–64 μg/mL MFC = 128–512 mg/mL |
Fe2O3 NPs (10–30 nm) [30] |
Trichothecium roseum, Cladosporium herbarum, P. chrysogenum, A. alternata, A. niger |
Inhibition of spore germination |
MIC = 0.063–0.016 mg/mL |
Fe3O4 NPs (70 nm) [31] |
C. albicans |
Inhibition of cell growth and biofilm formation |
MIC = 100 ppm MFC = 200 ppm |
Cu-BTC (10–20 µm) [32] |
C. albicans, A. niger, A. oryzae, F. oxysporum |
ROS producing, the damage of the cell membrane |
Inhibition of C. albicans colonies is 96% by 300 ppm and up to 100% by 500 ppm. Inhibition growth of F. oxysporum and A. oryzae is 30% with 500 ppm. No significant effect on the A. niger growth. |
HKUST-1 or HKUST-1 NPs (doped with NPs of Cu(I)) (49–51 nm) [33] |
A. niger, F. solani, P. chrysogenum |
Appearance of Cu+2 inhibiting of cell growth |
100% growth inhibition of F. solani by 750–1000 ppm and P. chrysogenum by 1000 ppm; for A. niger—no inhibition |
[Cu2(Glt)2(LIGAND)] (H2O) [34] |
C. albicans, A. niger spores |
The apoptosis-like fungal cell death, ROS production |
50–70% death of C. albicans and 50–80% germination inhibition of A. niger at 2 mg/mL of the MOFs |
MIL-53(Fe) and Ag@MIL-53(Fe) composite [35] |
A. flavus |
Inhibition of cell growth |
MIC = 40 μg/mL for the MIL-53(Fe); MIC = 15 μg/mL for the Ag@MIL-53(Fe) |
MOF on the basis of Ce and 4,4′,4″-nitrilotribenzoic acid [11] |
A. flavus, A. niger, Aspergillus terreus, C. albicans, Rhodotorula glutinis |
Enzyme-like activity: catalase, superoxide dismutase, and peroxidase |
Inhibition efficiency of 93.3–99.3% based on the colony-forming unit method |
TiO2 co-doped with nitrogen and fluorine (200–300 nm) [12] |
F. oxysporum |
Peroxidase-like activity, production of ROS under light irradiation |
100% inhibition of fungal growth |
Fe3O4@MoS2-Ag (~428.9 nm) [36] |
C. albicans |
Peroxidase-like activity |
80% damage of cell membranes |
CoZnO/MoS2 nanocomposite [37] |
A. flavus |
Peroxidase-like activity under light irradiation |
MIC = 1.8 mg/mL |
This entry is adapted from the peer-reviewed paper 10.3390/ijms241411359