Metal Nanoparticles as An Alternative to Antimycotics

Metal Nanoparticles as An Alternative to Antimycotics: Comparison

Please note this is a comparison between Version 4 by Jessie Wu and Version 3 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 nanoparticles (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.

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)	Type of NP	Shape
Organism(s) Tested	MIC	₅₀	(µg/mL)	Reference
Ag	Spherical
NR
Candida albicans
(
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

MIC, minimal inhibitory concentration; NR, Not reported; LMW, Low-molecular-weight; HMW, High-molecular-weight.

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	MIC	Size (nm)₈₀	Organism(s) Tested (µg/mL)	Reference
Activity (mm)	Reference
Ag	Spherical
AuNP + SnCl	3	₂ as reducing agent	Saccharomyces cerevisiae (KCTC 7296) Trichosporon beigelii (KCTC 7707) Candida albicans (ATCC 90028)	Polygonal, almost spherical30–50	Candida albicans (n = 30) Candida glabrata (n2	= 30)	5–50Candida tropicalis (	Candida albicans Candida tropicalisFusarium oxysporumn = 30)	4 9 9	Candida glabrata	Fusarium culmorum16 16	25 ^[23]
	16	^[	²	20	^]
^[	²⁴	^]		Spherical	1–21	Candida albicans Candida glabrata Candida parapsilosis Candida tropicalis Fusarium solani Fusarium moniliforme Fusarium oxysporum Aspergillus flavus Aspergillus fumigatus Aspergillus terrus Sporothrix schenckii Cryptococcus neoformans	0.25 0.125 0.25 0.125 1 2 4 1 2 2	Ag 0.25 0.25	Cubical	40–50	Candida albicans (n = 30) Candida glabrata
AuNP + NaBH₄ as reducing agent	(	n	= 30) Candida tropicalis (n = 30)	Spherical	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	Shape	Size (nm)	Organism(s) Tested	MIC₉₀ (µg/mL)	Reference
LMW Chitosan NP ± 1 mg/mL chitosan	Spherical	174 ± 38.47	Candida albicans Fusarium solani Aspergillus niger	250 1000 NR	19^[25]	^[
1		7		7	^[3
HMW Chitosan NP ± 1 mg/mL chitosan	^]
Spherical	210 ± 24.54	Candida albicans		AgFusarium solani Aspergillus niger	1000	Polygonal	35 ± 15	Candida tropicalis 500 ^[23]
NR	^[	²⁵	^]	Saccharomyces boulardii	25 µg/mL → >95 50 µg/mL → >95 25 µg/mL → <50 50 µg/mL → >95	^[		Spherical	5	Candida albicans (324LA/84) Candida glabrata (ATCC 90030) Candida albicans (ATCC 10321) Candida glabrata (D1)	0.4–0.8 0.4–0.8	Ag0.8–1.6 1.6–3.3	Wires	250–300	Candida albicans (n = 30) Candida glabrata (n = 30) Candida tropicalis (^[4]
n	= 30)	5		12 11	^[23]
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	Au	Cubical	30–50Aspergillus flavus Aspergillus fumigatus	Candida albicans (n = 30) Candida glabrata (n = 30) Candida tropicalis100 100	(n = 30)	3 10 11^[	^[23]
HMW Chitosan NP ± 2 mg/mL chitosan	⁵	^]
³¹	^]
Ag	Spherical	5	Colletotrichum gloeosporioides	13 µg/mL → 73 26 µg/mL → 82 56 µg/mL → 89	^[32]	Spherical	263 ± 86.44	Candida albicans Fusarium solani Aspergillus niger	857.2 857.2 1714	^[25]
Ag	Spherical	24	Colletotrichum gloeosporioides	13 µg/mL → 74 26 µg/mL → 82 56 µg/mL → 89	^[32]		Spherical	Au	Spherical	35–50
LMW Chitosan NP ± 3 mg/mL chitosan	25	Candida albicans	(I) Candida albicans (II)	Spherical Candida parapsilosis Candida albicans	255 ± 42.81Candida tropicalis	(n = 30) Candida glabrata (n = 30) Candida tropicalis (n = 30)	Candida albicans Fusarium solani
ZnO		Aspergillus niger	0.42	0.21 1.690 0.840	8	Spherical 13 12	607.2 1214^[6	30–45^]
^[	²³	^]
	NR	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	^[25]	3 mmol/L, day 10 → 14.1	^[33]		Spherical	5–20	Trichosporon asahii (CBS2479) Trichosporon asahii
Ag	(BZ701)		Trichosporon asahii (BZ702) Trichosporon asahii (BZ703) Trichosporon asahii (BZ704) Trichosporon asahii	NR (BZ705) Trichosporon asahii (BZ705R) Trichosporon asahii (BZ901) Trichosporon asahii (BZ902) Trichosporon asahii (BZ121) Trichosporon asahii (BZ122)	AuTrichosporon asahii	Wires (BZ123)	300–500 Trichosporon asahii (BZ124) Trichosporon asahii (BZ125) Trichosporon asahii (CBS8904)	Candida albicans	NR (n = 30) Candida glabrata (n = 30) Candida tropicalis (	Rhizoctonia solanin
HMW Chitosan NP ± 3 mg/mL chitosan	= 30)	Spherical	7	301 ± 72.85	Candida albicans Fusarium solani Aspergillus nigerTrichosporon asahii (CBS7137) Trichosporon asahii (CBS8520)	(AG1) Rhizoctonia solani (AG4) Macrophomina phaseolina Sclerotinia sclerotiorum Trichoderma harzianum Pythium aphanidermatum0.50 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	15 15	607.2 1214.3 ^[7]
2428.6	6 µg/mL → 75		8 µg/mL → 80	10 µg/mL → 90 12 µg/mL → 90 14 µg/mL → 90 16 µg/mL → 100 6 µg/mL → ≥90 8 µg/mL → ≥90 10 µg/mL → ≥90 12 µg/mL → 100	^[23]
	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	^[25]	12 µg/mL → 100 14 µg/mL → 100	^[27]	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	^[34]		Spherical	15–25	ZnOCandida albicans (ATCC 10231) Candida albicans (ATCC 90028)	Spherical	20–40	Candida albicans (
Fusarium oxysporum	Day 2: 10.4 Day 4: 9.6	n	Candida glabrata (ATCC 90030) Candida parapsilosis (ATCC 22019)	= 125)1.56	8.2	^[21]	^[27]
Ag	Cubical	40–50	Candida albicans (n
Ag	= 30)		Candida glabrata (n = 30)	6.25 3.12 6.25	Candida tropicalis (n = 30)	8 30 31^[8]
Spherical	^[	²³	^]	10–20	Bipolaris sorokiniana	≥2 µg/mL → 100	^[35]		Spherical	25	Candida albicans (I) Candida albicans (II) Candida parapsilosis
161 ± 44
Colletotrichum gloeosporioides
(from papaya)

Colletotrichum gloeosporioides
ZnO
Ag	Spherical	30–50	Candida albicans (n = 30) Candida glabrataCandida tropicalis	(n = 30) Candida tropicalis27 27 27 27	^[6]
(	n	= 30)	11	37
Ag		35
Pd	Spherical	350	SphericalFusarium oxysporum	Day 2: 1.5	1–9 Day 4: 1.3^[23]	Aspergillus flavus
^[	²⁷	^]	Spherical to polyhedric	Ag73.72	Wires	250–300	Candida albicans (n = 30) Candida glabrata (n = 30) Candida tropicalis (n = 30)	21 51 48	^[23]
Pd	Spherical	550	Fusarium oxysporum	Day 2: 3.8 Day 4: 3.3	^[27]	Au	Cubical	30–50	Candida albicans (n = 30) Candida glabrata (n = 30) Candida tropicalis (n = 30)	10 45 46	^[23]
ZnO	Spherical	20–40	Candida albicans (
CuO	Spherical	3–30	Fusarium equiseti	²⁶	^]
n
= 125)
17.76
^[
²¹
^]

ZnO
NR
Pd	Spherical	200	Colletotrichum gloeosporioides	Day 2: 3.6 Day 4: 1.6	^[27]
Pd	Spherical	200	Fusarium oxysporum	Day 2: 12.2 Day 4: 10.9	^[27]
Pd	Spherical
Pd	Spherical	5 µg/mL → 0		15 µg/mL → 30		25 µg/mL → 58 35 µg/mL → 85 45 µg/mL → 98 60 µg/mL → 100	^[36]	Nystatin/MgO/CuO	Spherical	8000–10000	Candida albicans (AH201) Candida albicans (AH267)	24.5 ± 1.7 14.3 ± 1.2	^[	Au	Spherical	35–50	Candida albicans (n = 30) Candida glabrata (n = 30) Candida tropicalis (n = 30)	15 47 48	^[23]
220	Colletotrichum gloeosporioides	Day 2: 7.9		Day 4: 6.3	^[27]	Trichophyton rubrum (n = 8) Trichophyton rubrum (ATCC MYA 4438)	0.5–2.5 <0.25
220	PEI¹/Ag	^[	⁹	^]	^[27]
Spherical	20.6	Rhizopus arrhizus	1.6 µg/mL → 97	^[	^37]		Spherical	76.14	Trichophyton rubrum (n = 8) Trichophyton rubrum (ATCC MYA 4438)	>7.5 >7.5	^[9]
²⁸	^]
PEI²		Spherical	100.6	Trichophyton rubrum
/Ag	Spherical	4.24		6.5 µg/mL → 94		Nystatin	Spherical (	8000–10000n = 8)	Candida albicansTrichophyton rubrum (ATCC MYA 4438)	(AH201) Candida albicans0.5–5 0.5	(AH267)
SiO	0.41 ± 0.23		0.5 ± 0.21	^[	^9]
₂	^[	²⁸	Spherical	^]	9.92–19.8	Rhizoctonia solani	100 µg/mL → 93–100	^[38]		NR	NR	Fusarium graminearum	4.68	^[	Au^10]
Wires	300–500	Candida albicans	(n = 30) Candida glabrata (n = 30)
MgO/CuO	Spherical	Candida tropicalis	8000–10000 (n = 30)	Candida albicans (AH201) Candida albicans (AH267)30 70 73	19.2 ± 1.6 1.3 ± 0.61	^[28]		NR	NR	Candida albicans (I) Candida albicans (II) Candida parapsilosis Candida tropicalis	0.42 0.21 1.69 0.84	^[6]
(from avocado)
TiO₂/BPE B		NR	NR	Candida albicans (I) Candida albicans (II) Candida parapsilosis Candida tropicalis	NR	Candida albicans (n = 10)0.052 0.1 0.84 0.42	^[6]
	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]
11.3

Fusarium oxysporum
Day 2: 5.1
	Day 4: 4.7
Pd	Spherical	250	Colletotrichum gloeosporioides	Day 2: 2.4 Day 4: 0.7
Pd	Spherical	250
^[
²³
^]
NR
NR	Candida albicans	(ATCC 14053)	11.2 ± 0.02	^[	^29]
312
TiO₂/BPE C	NR	NR	Candida albicans (ATCC 14053)	15.9 ± 0.04	^[29]

TiO₂/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]
312
TiO₂/BPE B	NR	NR	Penicillum chrysogenum (MTCC 5108)	10.2 ± 0.05	^[29]
TiO₂/BPE C	NR	NR	Penicillum chrysogenum (MTCC 5108)	18.0 ± 0.03	qAg	Spherical	2–3	Candida albicans
^[
¹⁶
^]
^[	²⁹	^]	0.07	^[	^12]
TiO₂/BPE D	NR	NR	Penicillum chrysogenum (MTCC 5108)	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	9 ± 3.9	Candida albicans (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, 1000 °C calcination	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).

NR
15.0 ± 0.04
^[
²⁹
^]
TiO
₂
/BPE E
NR
NR
Penicillum chrysogenum
(MTCC 5108)	13.5 ± 0.08	^[	²⁹	^]

BPE, Brahmi plant extract; NR, Not reported.

Table 6. Activities of NPs tested on different fungal species expressed as a percentage.

Type of NP	Shape	Size (nm)	Organism(s) Tested	Activity (%)	Reference
Ag	NR	20–100	Cladosporium cladosporioides Aspergillus niger	50 µg/mL → 90 50 µg/mL → 70	^[30]
ZnO/MgO

70 °C synthesis, 500 °C calcination
Flakes

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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