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Metal Nanoparticles as An Alternative to Antimycotics: Comparison
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Please note this is a comparison between Version 3 by Jessie Wu and Version 2 by Jessie Wu.

Fungi were initially included as a part of Kingdom Plantae but in 1969 were grouped into Kingdom Fungi, which comprises diverse groups with different morphologies, such as unicellular yeasts and multicellular organisms. The rate of antifungal resistance development has been called “unprecedented”. This is because immunocompromised individuals are at a higher risk of fungal infections than healthy individuals. Moreover, medical advancements over the past few decades and the HIV epidemic have increased the number of immunocompromised people, which has, in turn, shifted fungal infections from being an infrequent cause of disease to being an important contributor to human morbidity and mortality worldwide. There are six antifungal drug classes, and this scarcity, combined with the increasing resistance, has led to the need for novel treatments. The appearance of resistant species of fungi to the existent antimycotics is challenging for the scientific community. One emergent technology is the application of nanotechnology to develop novel antifungal agents. Metal nanoparticles (NPs) have shown promising results as an alternative to classical antimycotics.

  • nanoparticles
  • metals
  • ROS

1. Nanoparticle Formulation as Antifungal Agents

There is a need for novel antifungal treatments as currently available options are lacking. It is worth noting that the idea of increased potential future resistance is worrying as fungi are eukaryotes, as are their most common hosts found in Kingdoms Animalia and Plantae. That is to say, the eukaryotic hosts of pathogenic fungi have similarities in metabolism and protein structure, and finding targets to differentiate organisms becomes more complicated [1].
Nanotechnology has rapidly progressed over the past few decades and using NPs as potential antifungals have been an expanding field of interest. The present study summarized the literature from 2005 until 2022 regarding the NP formulations that showed antifungal activity (Table 1, Table 2, Table 3, Table 4, Table 5 and Table 6). A summary of the different types of metallic NPs studied is shown in Figure 1.
Nanomaterials 12 04470 g004 550
Figure 1. Different types of metallic NPs developed against fungi.
Table 1. Activities of NPs tested on different fungal species expressed in MIC100 (µg/mL).
Type of NP Shape Size (nm) Organism(s) Tested MIC100 (µg/mL) Reference
Size (nm) Organism(s) Tested MIC50 (µg/mL) Reference
Ag Spherical 3 Saccharomyces cerevisiae (KCTC 7296)

Trichosporon beigelii (KCTC 7707)

Candida albicans (ATCC 90028)		 2
Ag Spherical 30–50 Candida albicans (n = 30)

Candida glabrata (n = 30)

Candida tropicalis (n = 30)		 4

9

9		[
n
= 10)
5
[
22]
MIC, minimal inhibitory concentration; NR, Not reported.
Table 3. Activities of NPs tested on different fungal species expressed as MIC80 (µg/mL).
Type of NP Shape Size (nm) Organism(s) Tested
3–20
Candida albicans

Candida tropicalis

Candida glabrata		 4

4

4		 [24]
MIC, minimal inhibitory concentration.
Table 4. Activities of NPs tested on different fungal species expressed as MIC90 (µg/mL).
Type of NP ShapeMIC80 (µg/mL) Size (nm) Organism(s) Tested MICReference
90 (µg/mL) Reference
Table 5. Activities of NPs tested on different fungal species expressed as the zone of inhibition (mm).
Type of NP Shape Size (nm) Organism(s) Tested Activity (mm) Reference
Type of NP Shape Size (nm) Organism(s) Tested Activity (%) Reference
2]
[23]
AuNP + SnCl2 as reducing agent Polygonal, almost spherical
CuO Spherical5–50 Candida albicans

Candida tropicalis

Candida glabrata		 16

16

16
LMW Chitosan NP ± 1 mg/mL chitosan Spherical 174 ± 38.47 Candida albicans

Fusarium solani

Aspergillus niger		 250 3–30 Fusarium equiseti

Fusarium oxysporum

Fusarium culmorum

1000[24]		 25

  Spherical 1–21 Ag Cubical 40–50 Candida albicans (


NR 20

19 [26] Candida albicans
Ag NR 20–100 Cladosporium cladosporioides

[25] Aspergillus niger 50 µg/mL → 90

50 µg/mL → 70		 [30]


Candida glabrata

n = 30) AuNP + NaBH4 as reducing agentCandida parapsilosis


Candida glabrata
Candida tropicalis


Fusarium solani

Fusarium moniliforme

Fusarium oxysporum

Aspergillus flavus

Aspergillus fumigatus

Aspergillus terrus

Sporothrix schenckii

Cryptococcus neoformans		 (0.25 Sphericaln = 30)

Candida tropicalis (n = 30)

0.125

0.25

0.125

1

2

4

1

2

 1

7

7		 Pd[ Spherical 200 35 ± 15 Candida tropicalis

Saccharomyces boulardii2

0.25

0.25		 [ 25 µg/mL → >95

3]
23 Colletotrichum gloeosporioides] Day 2: 3.6

Day 4: 1.6		 50 µg/mL → >95

25 µg/mL → <50

50 µg/mL → >95		[27 [31]   Spherical 5 Candida albicans Ag (324LA/84)

Candida glabrata		 Wires (ATCC 90030)

Candida albicans		 250–300 (ATCC 10321)

Candida glabrata (D1)		 Candida albicans (n = 30)

Candida glabrata (n = 30)

Candida tropicalis (0.4–0.8

0.4–0.8

0.8–1.6

1.6–3.3		 n = 30) 5

12

11[4]
[23]
Ag Spherical 5 Colletotrichum gloeosporioides 13 µg/mL → 73

26 µg/mL → 82

56 µg/mL → 89		 [32] Au Cubical 30–50 Candida albicans (n = 30)

Candida glabrata (n = 30)

Candida tropicalis (n = 30)		 3

10

11		 [23]
Au Spherical 35–50 Candida albicans (n = 30)

Candida glabrata (n = 30)
HMW Chitosan NP ± 1 mg/mL chitosan Spherical 210 ± 24.54 Candida albicans

Fusarium solani

Aspergillus niger		 1000

500

NR		 [25]
LMW Chitosan NP ± 2 mg/mL chitosan Spherical 233 ± 41.38 Candida albicans

Fusarium solani

Aspergillus niger		 857.2

857.2

NR		 [25]   Spherical 7
HMW Chitosan NP ± 2 mg/mL chitosan Spherical Ag263 ± 86.44Aspergillus flavus

 Candida albicans

Ag]
Polygonal Fusarium oxysporum Day 2: 12.2

Day 4: 10.9		 Aspergillus fumigatus Fusarium solani

Aspergillus niger100

100		 [5]
857.2

857.2

1714 [25
Pd] Spherical 220 Colletotrichum gloeosporioides SphericalDay 2: 7.9

Day 4: 6.3		 [ 24 Colletotrichum gloeosporioides 13 µg/mL → 74

26 µg/mL → 82

56 µg/mL → 89		27] [32]   Spherical

Candida tropicalis (n = 30)		 8

13

12		 [23]
LMW Chitosan NP ± 3 mg/mL chitosan Spherical 255 ± 42.81
Fusarium oxysporum Day 2: 5.1

Day 4: 4.7		25 Candida albicans (I)

Candida albicans (II)

Candida parapsilosis

Candida tropicalis		 Candida albicans

Fusarium solani

Aspergillus niger0.42

0.21

1.690

0.840		 607.2

1214

[6]
NR [25]
ZnO Spherical 30–45 Erythricium salmonicolor 12 mmol/L, day 7 → 71.3

12 mmol/L, day 10 → 51.1

9 mmol/L, day 7 → 58.3

9 mmol/L, day 10 → 44.6

6 mmol/L, day 7 → 48.9

6 mmol/L, day 10 → 23.6

3 mmol/L, day 7 → 36.9

3 mmol/L, day 10 → 14.1		 [33]   Spherical 5–20 Trichosporon asahii Au (CBS2479) Wires 300–500

 Candida albicansTrichosporon asahii (BZ701)

Trichosporon asahii (BZ702)

Trichosporon asahii (BZ703)

Trichosporon asahii
Ag (BZ704)

Trichosporon asahii (BZ705)

(n = 30)

Candida glabrataTrichosporon asahii		 NR (BZ705R)

Trichosporon asahii (BZ901)

Trichosporon asahii (BZ902)

Trichosporon asahii (BZ121)

Trichosporon asahii (BZ122)

Trichosporon asahii (BZ123)

Trichosporon asahii (BZ124)

Trichosporon asahii (BZ125)

Trichosporon asahii (CBS8904) (n = 30)

Candida tropicalis (
HMW Chitosan NP ± 3 mg/mL chitosan Sphericaln 301 ± 72.85

Trichosporon asahii (CBS7137)

Trichosporon asahii (CBS8520)		 NR = 30) Rhizoctonia solani (AG1)0.50

 Candida albicans

Fusarium solani

Aspergillus niger










Rhizoctonia solani
(AG4)












Macrophomina phaseolina











Sclerotinia sclerotiorum











Trichoderma harzianum











Pythium aphanidermatum		0.67

0.50

1.00

0.67

0.50

0.50

0.67

1.00

0.83

0.67

0.50

0.67

0.83

0.50

0.67

0.67		 7 6 µg/mL → 75

8 µg/mL → 80

10 µg/mL → 90

12 µg/mL → 90[7]


14 µg/mL → 90

16 µg/mL → 100

   Spherical 15–25 Candida albicans (ATCC 10231)

Candida albicans (ATCC 90028)

Candida glabrata (ATCC 90030)

Candida parapsilosis (ATCC 22019)		 1.56

6.25

3.12

Pd Spherical

 25015

15		 [23]
607.2

1214.3

2428.6 [ Colletotrichum gloeosporioides25] Day 2: 2.4

Day 4: 0.7		 6 µg/mL → ≥90

8 µg/mL → ≥90

10 µg/mL → ≥90

12 µg/mL → 100

14 µg/mL → 100

16 µg/mL → 100

6 µg/mL → 100

8 µg/mL → 100

10 µg/mL → 100

12 µg/mL → 100

14 µg/mL → 100

16 µg/mL → 100

6 µg/mL → ≥95

8 µg/mL → 100

10 µg/mL → 100

12 µg/mL → 100

14 µg/mL → 100

16 µg/mL → 100

6 µg/mL → 80

8 µg/mL → 84

10 µg/mL → 90

12 µg/mL → 100

14 µg/mL → 100

16 µg/mL → 100

6 µg/mL → 100

8 µg/mL → 100

10 µg/mL → 100

12 µg/mL → 100

14 µg/mL → 100

16 µg/mL → 100		[27] [34] 6.25 ZnO Spherical 20–40 Candida albicans (n = 125)
Ag Cubical 40–50 Candida albicans Fusarium oxysporum ( Day 2: 10.4

Day 4: 9.6n = 30)

Candida glabrata (n[8]
= 30)

8.2 Candida tropicalis (n = 30) 8

30

31		[ [23]
Ag Spherical 10–20 Bipolaris sorokiniana ≥2 µg/mL → 100 [35]   Spherical 25 Candida albicans (I)

Ag SphericalCandida albicans (II)

Candida albicansCandida parapsilosis

 1–9Candida tropicalis (n = 30)27

27

27

 Aspergillus flavus27
Pd

Candida glabrata 5 µg/mL → 0

15 µg/mL → 30

25 µg/mL → 58		[6]
Spherical (n = 30)

35 µg/mL → 85

   Spherical to polyhedric 73.72 Trichophyton rubrum (n = 8)

Trichophyton rubrum (ATCC MYA 4438)


Colletotrichum gloeosporioides
(from avocado)
312




312
[
16
]
21]
ZnO NR NR Candida albicans (
Ag Spherical 30–50

Candida tropicalis (n = 30)		 11

37

35		 45 µg/mL → 98

[23]
350 Fusarium oxysporum Day 2: 1.5

Day 4: 1.3 60 µg/mL → 100[27] [36] 0.5–2.5

<0.25		 Ag Wires
PEI1/Ag Spherical250–300 Candida albicans (n = 30)

Candida glabrata (n
Pd = 30)

Candida tropicalis (n = 30) Spherical21

 20.651

[9]
48 [23]
550 Fusarium oxysporum Day 2: 3.8

Day 4: 3.3 [ Rhizopus arrhizus 1.6 µg/mL → 9727] [37]   Spherical 76.14 AuTrichophyton rubrum Cubical ( 30–50n = 8)

 Candida albicansTrichophyton rubrum (ATCC MYA 4438) (
Nystatin/MgO/CuO Sphericaln
PEI2/Ag8000–10000 = 30)

Candida glabrata (n = 30)

Candida tropicalis (n = 30)		>7.5

>7.5		 Candida albicans (AH201)

Candida albicans (AH267)10

45

46[9		 Spherical]
[23]
24.5 ± 1.7 4.24

14.3 ± 1.2 [28]   6.5 µg/mL → 94     Spherical 100.6 Trichophyton rubrum Au ( Sphericaln 35–50 = 8)

Trichophyton rubrum (ATCC MYA 4438)		 Candida albicans (n = 30)

0.5–5

0.5		 [9]
Candida glabrata (
Nystatin Sphericaln 8000–10000 = 30)

Candida tropicalis (n = 30)		 Candida albicans (AH201)

Candida albicans (AH267)15

47

48		 [23]  
0.41 ± 0.23
SiO2 Spherical 9.92–19.8 Rhizoctonia solani 100 µg/mL → 93–100 [38]NR NR Fusarium graminearum Au Wires 300–500 Candida albicans (n = 30)

Candida glabrata (4.68		 n = 30)

Candida tropicalis (n = 30)[10]
30

70

73 [23]
0.5 ± 0.21 [28]
MgO/CuO Spherical 8000–10000 Candida albicans (AH201)

Candida albicans (AH267)		 19.2 ± 1.6

1.3 ± 0.61		 [28]   NR NR Candida albicans (I)

Candida albicans (II)

 ZnOCandida parapsilosis Spherical

 20–40Candida tropicalis Candida albicans (n = 125)0.42

0.21

1.69

0.84		 [6]
17.76
TiO2/BPE B[ NR21]
NR Candida albicans (ATCC 14053) 11.2 ± 0.02 [29]   NR NR Candida albicans (I)

Candida albicans (II)

Candida parapsilosis

Candida tropicalis		 0.052 ZnO NR
TiO2NR /BPE C NRCandida albicans (n = 10)

0.1

0.84

0.42		 [6]
11.3     NR NR Candida albicans (I)

Candida albicans (II)

Candida parapsilosis

Candida tropicalis		 3.38

3.38

3.38

3.38		 [6]
  NR 20–25 Aspergillus niger

Candida albicans

Cryptococcus neoformans		 25

6

3		 [11]
  NR NR Fusarium graminearum 12.5 [10]
Ag/ZnO Spherical 7/477 Aspergillus flavus

Aspergillus fumigatus		 50/10

50/10		 [5]
qAg Spherical 2–3 Candida albicans 0.07 [12]
Cu Spherical 10–40 Candida albicans (ATCC 10231)

Candida albicans (Clinical strain C)

Candida albicans (Clinical strain E)		 129.7

1037.5

518.8		 [13]
  Wires 20–30 µm, 30–60 nm diameter Candida albicans (ATCC 10231)

Candida albicans (Clinical strain C)

Candida albicans (Clinical strain E)		 260.3

260.3

260.3		 [13]
γ-Fe2O3/Ag NR 20–40 (Ag) + 5 (γ-Fe2O3) Candida albicans (I)

Candida albicans (II)

Candida tropicalis (5)

Candida parapsilosis (6)		 1.9

1.9

31.3

31.3		 [14]
Fe3O4/Ag NR ~5 (Ag) + ~70 (Fe3O4) Candida albicans (I)

Candida albicans (II)

Candida tropicalis (5)

Candida parapsilosis (6)		 1.9

1.9

3.9

7.8		 [14]
GO/Ag Spherical 10–35 Fusarium graminearum 9.37 [10]
HA/Ag Rod/Spherical 12–27 Candida albicans 62.5 [15]
MgO

500 °C calcination		 Flaked layers 52 ± 18 Colletotrichum gloeosporioides (from papaya)

Colletotrichum gloeosporioides (from avocado)		 156

312		 [16]
MgO

1000 °C calcination		 Flaked layers 96 ± 33 Colletotrichum gloeosporioides (from papaya)

Colletotrichum gloeosporioides (from avocado)		 312

312		 [16]
Pd Spherical
MIC, minimal inhibitory concentration; NR, Not reported; LMW, Low-molecular-weight; HMW, High-molecular-weight.
NR
Candida albicans
(ATCC 14053)
15.9 ± 0.04
[
29
]
9 ± 3.9
TiO
2/BPE D NR NR Candida albicans (ATCC 14053) 13.5 ± 0.04 [29]
TiO2/BPE E NR NR Candida albicans (ATCC 14053) 14.6 ± 0.01 [29]
Candida albicans
TiO2/BPE B NR NR Penicillum chrysogenum (MTCC 5108) 10.2 ± 0.05 [29]
ZnO/MgO
TiO2/BPE C NR NR Penicillum chrysogenum (MTCC 5108) 18.0 ± 0.03 [29]


TiO2/BPE D NR NR Penicillum chrysogenum (MTCC 5108) 15.0 ± 0.04 [29]
70 °C synthesis, 1000 °C calcination
TiO2/BPE E NR NR Penicillum chrysogenum (MTCC 5108) 13.5 ± 0.08 [29]
(ATCC 10231)


Aspergillus niger 212.5

200 [17]
Se Spherical 80–200 Candida albicans (ATCC 76615)

Candida albicans (ATCC 10231)		 100

70		 [18]
Se Spherical 37–46 Aspergillus fumigatus (TIMML-025)

Aspergillus fumigatus (TIMML-050)

Aspergillus fumigatus (TIMML-379)		 0.5

0.5

1		 [19]
Silica/AmB NR 5 Candida albicans

Candida krusei

Candida parapsilosis

Candida glabrata

Candida tropicalis		 100

1000

1000–2000

300

100		 [20]
TiO2/Ag + NaHB4 NR 250–300 Aspergillus niger

Candida albicans

Cryptococcus neoformans		 25

12.5

12.5		 [11]
TiO2/Ag + UV NR 250–300 Aspergillus niger

Candida albicans

Cryptococcus neoformans		 12.5

6

3		 [11]
ZnO Spherical 20–40 Candida albicans (n = 125) 0.2–296 [21]
  Spherical 477 Aspergillus flavus

Aspergillus fumigatus		 20

20		 [5]
ZnO

500 °C calcination		 Spherical + cylindrical 51 ± 13 Colletotrichum gloeosporioides (from papaya)

Colletotrichum gloeosporioides (from avocado)		 156

312		 [16]
ZnO

1000 °C calcination		 Hexagonal bars 53 ± 17 Colletotrichum gloeosporioides (from papaya)

Colletotrichum gloeosporioides (from avocado)		 156

312		 [16]
ZnO/Mg(OH)2

25 °C synthesis		 Flakes + bars 54 ± 17 Colletotrichum gloeosporioides (from papaya)

Colletotrichum gloeosporioides (from avocado)		 156

312		 [16]
ZnO NP

25 °C synthesis		 Hexagonal bars + ovoidal 63 ± 18 Colletotrichum gloeosporioides (from papaya)

Colletotrichum gloeosporioides (from avocado)		 312

312		 [16]
ZnO/Mg(OH)2

70 °C synthesis		 Flakes + bars 71 ± 22 Colletotrichum gloeosporioides (from papaya)

Colletotrichum gloeosporioides (from avocado)		 312

312		 [16]
ZnO

25 °C synthesis, hydrothermal		 Prisms with pyramidal ends 77 ± 31 Colletotrichum gloeosporioides (from papaya)

Colletotrichum gloeosporioides (from avocado)		 312

312		 [16]
ZnO/Mg(OH)2 NP

25 °C synthesis, hydrothermal 160 °C		 Flakes + bars 88 ± 30 Colletotrichum gloeosporioides (from papaya)

Colletotrichum gloeosporioides (from avocado)		 312

312		 [16]
ZnO/Mg(OH)2

70 °C synthesis, hydrothermal 160 °C		 Flakes + bars 98 ± 41 Colletotrichum gloeosporioides (from papaya)

Colletotrichum gloeosporioides (from avocado)		 312

312		 [16]
ZnO/MgO

25 °C synthesis, 500 °C calcination		 Flakes 139 ± 49 Colletotrichum gloeosporioides (from papaya)

Colletotrichum gloeosporioides (from avocado)		 312



312		 [16]
ZnO/MgO

70 °C synthesis, 500 °C calcination		 Flakes 161 ± 44 Colletotrichum gloeosporioides (from papaya)
Flakes 219 ± 39 Colletotrichum gloeosporioides (from papaya)

Colletotrichum gloeosporioides (from avocado)		 625

625		 [16]
ZnO NR NR Candida albicans (n = 10) 0.02–269 [22]
MIC, minimal inhibitory concentration; qAg, quantum silver; NR, Not reported; HA, hydroxyapatite.
Table 2. Activities of NPs tested on different fungal species expressed as MIC50 (µg/mL).
Type of NP Shape
BPE, Brahmi plant extract; NR, Not reported.
Table 6. Activities of NPs tested on different fungal species expressed as a percentage.
NR, Not reported; PEI1, polyethyleneimine 700,000 Da; PEI2, polyethyleneimine 65,000 Da.
NPs have unique physical and chemical properties compared to their larger counterparts because their small size leads to a high surface-to-volume ratio. NPs can be produced using the top-down technique, where small particles are formed from a more significant part, or the bottom-up technique, where small particles assemble from smaller pieces. The bottom-up approach is typically favored for the synthesis of NPs as it makes more homogeneous products with fewer defects and has parameters that are easier to control during fabrication. For example, altering compound surface charges can facilitate bottom-up processes such as interfacial electrostatic self-assembly [10]. As another example, the electrochemical synthesis of metal NPs can be utilized to avoid reducing chemicals and control size dispersion based on the cell electrode potential tuning [27]. This is interesting because usually, a bottom-up process requires a metal salt and a reducing agent, such as sodium borohydride or Sn(II) chloride [24][39].
There is no standardized approach for the fabrication of NPs, and they can be found in various shapes, sizes, compositions, and formulations. However, spherical AgNPs are the most popular. Ag has been known for centuries to possess antimicrobial properties [40]. We know today that AgNPs possess these same properties and unique optical, electrical, and other physical/chemical properties. It is proposed that a potential mechanism of toxicity of Ag comes from its ion release coupled with its catalytic oxidation abilities [41].
Combining different AgNPs can exhibit a synergistic effect [42]. For example, combinations of AgNPs with other oxides, such as maghemite (γ-Fe2O3) or magnetite (Fe3O4), can lead to NPs that possess the unique Ag features while incorporating the magnetic features included in the iron oxide compounds, such as controllable alterations through magnetic field manipulation [14]. Moreover, combining AgNPs with graphene-oxide (GO) produced nanosheets with a three- and a seven-fold increase in bacterial inhibition efficiency over their counterparts in one study [10]. However, in another, combining AgNPs with ineffective copper NPs (CuNPs), a synergistic effect was not measured but somewhat diminished the activity of the AgNPs [43].
Other types of oxides have been investigated as well. A study looking at the antifungal activity of metal(loid) oxides found that Al2O3, Mn3O4, SiO2, and SnO2 reduced cell viability in a dose-dependent manner, whereas In2O3 showed no toxicity, even at concentrations of 100 mg/L [44]. GO is also of interest and has been used in functionalization and investigated as it is a single-atom-thick and a 2D sp2-bonded carbon lattice with a large surface area [45]. This is important because a lattice will innately prevent aggregation as dispersion will be enhanced and remain during the usage of the particles. Thus, GO’s surfactant-like properties allow it to attach metal NPs to hyphal interfaces, forming nanosheets with concomitant mechanical damage due to their extremely sharp edges [10].
Other oxides, such as titanium dioxide (TiO2) NPs, have shown that the mechanism of antimicrobial ability requires visible light to affect [46][47]. The photocatalytic activity is based on hydroxyl radical generation. It is known that photocatalysis works through photons exciting electrons to the conduction band and forming electron-hole pairs. An alternative to increase the radical hydroxyl production is doping TiO2 with Ag, potentially by accepting the photoinduced electrons and holes with an increase in the degradation efficiency [47]. Another study found that undoped TiO2NPs did have some antifungal properties, but the combination with Ag enhanced their efficacy. Fungal species also play a role in the antifungal activity of NPs, e.g., Venturia inaequalis was more affected by undoped TiO2 than Fusarium solani. Still, the most effective nanomaterial was Ag-doped hollow TiO2NPs. However, this may have been because the hollow formulation was spherical, and the solid formulation shape was indiscernible in TEM imaging [47]. As shown in another study, TiO2NPs did not show activity unless doped with nitrogen (N) and fluorine (F) [46]. Lastly, zinc oxide (ZnO) NPs are a prevalent oxide formulation [48][49][50][51][52].
Green synthesis is a method of synthesizing NPs that is more biologically- and environmentally friendly. This is done by using biogenic sources such as plants, bacteria, or fungi and incorporating their naturally occurring innately-antimicrobial metabolites or compounds into or onto NPs, acting as stabilizers or removing the need for harsh chemical components [53][54]. Sometimes, the color of the NPs may change when using plant extracts to synthesize NPs. For instance, a change to red/brown may indicate the incorporation of saponins and phenolic compounds as stabilizing agents providing the reduction power during production [55]. In another study, encapsulated Cymbopogon martinii (ginger grass) essential oil (extracted through hydro distillation) rather than using plant extracts during formulation in chitosan NPs to exploit the oil’s antifungal properties against Fusarium graminearum [53].
NPs made with biogenic sources [8][9][18][30][52][54][55][56][57] can have an enhanced effect compared to NPs made only chemically [52]. The biogenic formulation can increase the antifungal effect via increased reactive oxygen species (ROS) production, cell membrane disintegration, spore reduction, gene expression changes, and mycelial destruction [8][18][19][50][52]. Upon altering parameters, biogenic sources may produce AgNPs less effective than their chemical-only counterparts. An important parameter is a biological source; for example, the use of the fungus Penicillium chrysogenum as part of the synthesis of AgNPs was more effective than A. oryzae, although still less effective than the chemical-only process [9]. The formulation process may differ from organism to organism; however, the metal ions are typically entrapped by or surrounded by compounds released from the microorganism and undergo reduction.
Since fungal culture is a lab-controlled environment, the parameters for the formulation of NPs are also controlled [58]. For example, He et al. hypothesized that during gold NPs (AuNPs) formation, the bacterium Rhodopseudomonas capsulate secrets NADH- and NADH-dependent enzymes. During the electron transfer from NADH by NADH-dependent reductase, Au (III) ions capture electrons and, as a result, are reduced to Au (0) [59]. This mechanism of NADH- and NADH-dependent enzymes is likely also present in fungi, as extracellular filtrate of F. oxysporum strains used for synthesis contained NADH-dependent nitrate reductase enzymes [60].
Fungal biomolecules can behave as stabilizing agents during the formulation process and help achieve spherical particles [9][54]. For instance, during AuNPs formulation, it was found that biomolecules >3 kDa were not able to reduce Au (III) to Au (0). Interestingly, when comparing the AuNPs formation ability of various fungal extractions, it was found that while extractions containing large biomolecules were not capable of forming NPs, others containing small components would make unstable NPs, likely due to the small components’ inability to act as stabilizing agents. Combining different fractions developed stable NPs with slightly increased sizes of ~30 nm, compared to previous sizes of ~8–30 nm. Thus, it was concluded that biomolecules <3 kDa, such as glucose or amino acids, are involved in reducing the metal, and biomolecules >3 kDa, such as proteins, are involved in the stabilization [54].

2. Antifungal Classes and Combination with Metal Nanoparticles

Currently, there are six antifungal drug categories, including four main antifungal drug classes: allylamines, azoles, echinocandins, and polyenes. Some literature will include the antimetabolite class [61][62] and, more recently, triterpenoids, such as ibrexafungerp, the first drug in the triterpenoid class [61][63].
Ergosterol and β-(1,3)-D-glucan are favored targets in antifungals, as these molecules are crucial for the survival of pathogenic fungi. These compounds are attractive because they are not produced by human cells (Table 7) [61]. Ergosterol is essentially the cholesterol equivalent in fungi and protozoa. Found in the cellular membrane, it is responsible for the membrane’s integrity and flexibility. Ergosterol is structurally similar to cholesterol aside from containing a double bond and additional methyl group in the alkyl side chain; this trans double bond means it is not saturated like cholesterol. There is also a second double bond at 7,8-position, alongside the 5,6-positioned double bond found in the cholesterol [64].
Table 7. Current antifungal classes and their mechanisms of action.
Class Examples Mechanism of Action
Allylamines Terbinafine

Naftifine		 Squalene epoxidase inhibition, responsible for conversion of squalene to ergosterol
Azoles Clotrimazole

Miconazole

Ketoconazole

Fluconazole

Itrazonacole		 C14-α demethylation inhibition of lanosterol, inhibiting ergosterol synthesis
Echinocandins Caspofungin

Micafungin

Anidulafungin		 β-(1,3)-D-glucan synthase inhibition, interfering with cell wall synthesis
Polyenes Amphotericin B

Nystatin

Candicidin		 Ergosterol binding, forming pores and causing leakage, inhibiting proper transport mechanisms
Antimetabolites Flucytosine Pyrimidine analogue, interfering with nucleic acid synthesis
Triterpenoids Ibrexafungerp β-(1,3)-D-glucan synthase inhibition, interfering with cell wall synthesis
As mentioned earlier, the second compound, β-(1,3)-D-glucan, is a fungal cell wall component.
Antifungal resistance is a problem that is increasing worldwide. This can arise due to many mechanisms, including gene upregulation [65] for cell wall component synthesis [66] or efflux pump synthesis [67], modification of target site [68], or development of biofilm [69], amongst others. For example, the overexpression of ERG11 in yeast or CYP51 in mold confers resistance through the overproduction of lanosterol 14-α demethylase, aiding cell wall building and maintenance [66][70]. Because NPs have numerous mechanisms of action, fungi would have to evolve in multiple ways to acquire resistance while maintaining homeostasis and survival. As it is difficult to combat the simultaneous antifungal mechanisms of NPs, even though some are similar to antifungals (e.g., gene regulation), it is unlikely that fungi would be able to become resistant, at the very least, not at the same rate as the current antifungals used today.
NPs can be synthesized and combined with antifungals to increase one or both of their antimycotic capabilities [8][20][28][56][57][71]. One study decorated SiNPs with amphotericin B (AmB) to create particles with antifungal ability that could adhere to surfaces and be reused up to 5 times. The NPs alone was 3–33 times less effective than AmB on their own, but the addition of the antifungal gave the NPs an antifungal ability stronger than that of 10 nm colloidal Ag [20]. This, paired with the ability to coat surfaces, makes the particles worth further investigation, particularly in coating medical devices. While many studies have shown the synergism of NPs combined with antifungal medications, the effect can vary based on which fungal species are being treated [56][57].
The addition of antifungals to NPs can also benefit efficacy in unexpected ways. It can increase the roughness of NPs surfaces, which may account for mechanical damage or increased surface areas [28]. When antifungals are enclosed in NPs rather than coated, this can reduce their toxicity, such as in the case of AmB, where hemolytic activity in mammalian red blood cells was reduced from approximately 66% to 30% [72]. Therefore, combining NPs with antifungals can enhance activity, alter the morphology of NPs, and reduce cytotoxicity in human cells. Also, NPs on their own can have stronger antimycotic abilities than traditional antifungals [12].


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