Phytochemicals With Antifungal

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Phytochemicals with antifungal properties: Cure from nature
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DOI: 10.21161/mjm
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Malaysian Journal of Microbiology, Vol 16(4) 2020, pp. xxx-xxx
DOI: http://dx.doi.org/10.21161/mjm. 190551
Malaysian Journal of Microbiology

Published by Malaysian Society for Microbiology
(In since 2011)
Phytochemicals with antifungal properties: Cure from nature

Amal A. M. Elgharbawy1*, Nurhusna Samsudin1, Farah Fadwa Benbelgacem2, Yumi Zuhanis Has-Yun Hashim1,
Hamzah Mohd. Salleh1 and Jacinta Santhanam3
1International
Institute for Halal Research and Training (INHART), International Islamic University Malaysia, P.O. Box 10,
50728 Kuala Lumpur, Malaysia.
2Department of Biotechnology Engineering, International Islamic University Malaysia, P.O. Box 10, 50728 Kuala Lumpur,
Malaysia.
3Biomedical Science Program, Faculty of Health Sciences, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul
Aziz, 50300 Kuala Lumpur, Malaysia.

Email: [email protected]
Received 12 August 2019; Received in revised form 8 January 2020; Accepted 2 March 2020
ABSTRACT
Aims: The exploration of natural products with innovative uses is dynamic and expanding rapidly. Medicinal plants have
fascinated many researchers that subsequently lead to research publications highlighting plant extracts with wide range
of secondary metabolites such as flavonoids, alkaloids, glycosides, quinones, terpenoids, tannins and saponins that
exhibit antimicrobial activities and disease control. The concentration of these bioactive compounds in each plant
species varies based on the pathosystem and environmental conditions. This study aims to uncover the various types of
phytochemicals with antifungal properties.
Methodology and results: Seven categories of plant-based antifungal compounds were reviewed, which are
terpenoids, saponins, phenolic compounds, coumarins, alkaloids, essential oils and peptides, with examples and
structures of some available compounds. The mechanism of action of each category of phytochemical was discussed.
Also, the impact of some compounds was explained and elaborated.
Conclusion, significance and impact of study: It is of a great importance to explore natural plant fighters against
fungal infection. Those active plant components do not only have antifungal properties, but they also help in the healing
process and some even exhibit anticancer activities. The development and knowledge of antifungal activities from plant
extracts have the potential for applications in antifungal therapy. Since the exact description of how antifungal
compounds function in the human body is still unclear more studies are required to unveil phytochemicals’ properties
and to elucidate their effects on living cells.
Keywords: Antifungal, phytochemical, secondary metabolite, natural products, minimum inhibitory concentration (MIC)
INTRODUCTION Chaetomium and Stachybotrys (Baxi et al., 2016) and few

species that are pathogenic to human. Candida,
A fungus belongs to eukaryotic organisms that embrace Aspergillus and Cryptococcus are pathogens that normally
both multicellular and unicellular microorganisms such as caused infection to humans (Karkowska-kuleta et al.,
molds and yeasts, as well as mushrooms. Fungi are 2009). However, fungi play an important role in an
classified as a kingdom, separated from other eukaryotic ecosystem and significantly contribute to biological
kingdoms of animals and plants. Pathogenic fungi cause stability such as in the form of insect symbionts,
diseases in humans and other organisms (Baxi et al., mycorrhizae and lichens. Several types of fungi break
2016). Fungi are ubiquitous microorganisms that can be down organic biomaterials such as complex
found everywhere. When airborne, fungi take the form of carbohydrates and contaminants such as petroleum,
spores, mycelia and hyphal fragments. When inhaled, xenobiotics and hydrocarbons. Thus, fungi play a vital part
such particles contribute to health effects in human, in the carbon cycle (Gulis et al., 2009).
including several diseases. Common fungi include There are two general groups of fungal pathogens,
Cladosporium, Epicoccum and Alternaria, to name a few. which are primary and opportunistic pathogens. Primary
Moreover, fungi that are associated with decay or indoor pathogens usually develop an environmental reservoir
water damage include Aspergillus, Penicillium, and infect individuals that encounter with a large dosage
*Corresponding author
xxx ISSN (print): 1823-8262, ISSN (online): 2231-7538
Malays. J. Microbiol. Vol 16(4) 2020, pp. xxx-xxx
of the fungi from the environment. Opportunistic activities (Sales et al., 2016). This review paper aimed to
pathogens provoke disease in hosts when their systemic uncover various plants with antifungal properties. It also
immunity has been innately dysfunctional, damaged, or reveals the mechanism of actions of several groups of
impaired. Fungal pathogenesis’s mechanisms are not antifungal compounds and their effect at the cellular level.
well-recognized as bacterial pathogens. Few fungi are
proficient pathogens in contrast to bacteria (Burik and
Magee, 2001).
Candida albicans is the foremost fungal pathogen to
humans. The infections with Candida are severe,
particularly for individuals with weak immune defense. C.
albicans can form highly ordered biofilms, microbial
colonies that are enclosed by extracellular matrix and they
are attached to a solid surface (Chandra et al., 2001). The
formation of C. albicans biofilms is troublesome to medical
practitioners, where the biofilm is normally found on an
implanted medical device (Uppuluri and Lopez Ribot,
2017). It may act as a reservoir for the pathogenic cells
that are resistant to host immune system and drugs that
may lead to invasive systemic infections of tissue, organ
and infect almost all inner organs, including lungs, kidney,
heart, liver, spleen and brain, causing fungemia and life-
threatening septicemia (Karkowska-kuleta et al., 2009).
Over 50% of the central venous catheters are infected by Figure 1: Number of publications in 2008 to 2019 duration
C. albicans biofilm with approximately 100,000 death and through Scopus search, using the keywords: “antifungal +
excess of $6.5 billion in expenditure annually in the United phytochemicals”, “antifungal + essential oils”, “antifungal +
States (Fox and Nobile, 2013). plant extract” and “antifungal activity”, as of 21st May
The development of C. albicans biofilm undergoes four 2020.
distinct phases. The formation of a biofilm begins with the
seeding step, where the cells adhere to a solid surface to SECONDARY METABOLITES WITH ANTIFUNGAL
form a basal layer of anchoring cells. This phase normally ACTIVITY
takes approximately 60-90 minutes. Next, is the early-
stage of filamentation, where the cells start to proliferate. Terpenoids
Following this is the formation of a complex network that
consists of several layers of cells such as hyphal cells, What are terpenoids?
pseudohyphal cells and round cells enclosed in an
extracellular matrix. This stage is called a biofilm Terpenoids are secondary metabolites that can be
maturation stage, which typically takes 24 hours to form. isolated from natural sources such as plants,
The last stage is the dispersal stage, where the round microorganisms, animals, insects, marines and
cells detach from the biofilm to seed a new site (Douglas, endophytes. Terpenoids compose of more than 40,000
2003). variations to date, which are still being explored. Most of
At present, the exploration of natural products with the terpenoids variations with biologically active properties
innovative uses are dynamic and expanding rapidly. are useful as therapeutics and preventive agents for
Medicinal plants have fascinated many researchers that several diseases, including cancer. Terpenoids exhibit
subsequently lead to research publications highlighting antifungal, antimicrobial, antiviral, antiparasitic,
plant extracts with wide range of secondary metabolites antispasmodic, antiallergenic, anti-inflammatory,
such as flavonoids, alkaloids, glycosides, quinones, immunomodulatory and antihyperglycemic properties
terpenoids, terpenoids, tannins and saponins that exhibit (Thoppil and Bishayee, 2011). Meanwhile, there are some
antimicrobial activities and disease control. Figure 1 terpenoids variations that are toxic and have a severe
shows the number of publications on antifungal, impact on the nervous system and the functional ability of
phytochemicals, essential oils and plant extract in the the human body (Mbaveng et al., 2014).
period 2008- 2019. The concentration of these bioactive Terpenoids are classified based on the number of
compounds in each plant species varies based on the C5H8 isoprene units (2-methylbuta-1,3-diene) and the
pathosystem and environmental conditions. A medicinal structural organization of carbons. The single isoprene
plant is in which one or more of its parts, contains unit accounts for most classes of terpenoids.
functional phytochemical, which can be isolated and Hemiterpenoids contains five carbons and one unit of
applied either for medicinal treatment or as a drug isoprene. The subsequent classes increase by five
constituent (Sofowora et al., 2013). To date, plant species carbons at a time and one isoprene unit, starting with
of Allium sativum L. (garlic), Glycyrrhiza glabra L. monoterpenes. The backbone and structure of terpenoids
(licorice) and Aloe vera (L.) Burm f. (aloe) are known to reported in this review are shown in Figure 2.
have bioactive natural products with significant antifungal

O CH3
CH2 CH3
H2C CH2
CH2
O O
CH3 O
CH3 O CH3
O O
Isoprene (unit) Parthenolide 1,10-Epoxyparthenolide
Building block
Sesquiterpenes Triterpinoid Oleanolic acid
H O H O CH3
H H
H3C OH H3C OH
O O
OH
H3C
H H
H3C CH3 CH2 H3C CH3
Warburganal Muzigadial Thymol
CH3 CH3 CH3

OH
O
H3C
O
H3C
O O
O
CH3 CH3 H3C CH3
O O
Arteannuin B Artemisinin Carvacrol

CH3
H2C CH3
H
H CH2
CH3 O
CH3 H CH3
O
CH3
CH3
HO
H
H3C CH3
Lupeol Costunolide
CH3 CH3
H3C CH3
CH3
H CH3
CH3 H
H3C CH3
H H
HO
Stigmasterol P-cymene
CH3
H3C CH3
CH3
H CH3
CH3 H
H H
HO
β-sitosterol

CH2
H3C CH3
CH3
OH CH3
CH3
O
H3CO
HO CO 2H OH
OH
O
H
CH2
Ascosteroside
HO 2C H3C
CH3 CH3
OH CH3
O
H
CH3
OH H3C O
O CH3
O
HO O
HO H
OH CH3
Enfumafungin
OH
H3C
CH3 OH
H3C OH
H3C
O
CH3
HO 2C O
H3C CH3
Arundifungin
CH3
H3C
CH3
HO 2C
H3C
CH3
OSO 3H
O H
H3C
O OH Ergokonin A
O
CH3 NH2
Figure 2: The isoprene building block of terpenoids and chemical structures of some terpenoids.

Most sesquiterpenes (C25H40) have anti-plasmodial potent antifungal activity of their own. Besides, terpenoid
and antimicrobial activities while some have antifeedant, phenols are efficacious not only on planktonic cells but
anticancer, anti-mycotoxigenic, antioxidant, anti- also on biofilms of C. albicans that are resistant to many
inflammatory, anti-protozoal and cytotoxic activities. antifungal drugs (Rao et al., 2010). Among all terpenoid
Costunolide, parthenolide and its derivative (1,10- phenols, carvacrol exhibited the strongest antifungal
epoxyparthenolide) from sesquiterpenes family were activity against C. albicans biofilms, with a minimum
recognized for their antimicrobial activities against inhibitory concentration, MIC of <0.03%. Aside from C.
Helminthosporium spp. Significant antifungal activities albicans, the terpenoid phenols were also able to inhibit
were also detected by warburganal and muzigadial, biofilms of several other strains of Candida, including C.
against Sclerotinia libertiana, Candida utilis, and glabrata, and C. parapsilosis. (Abdel-Massih et al., 2010).
Saccharomyces cerevisiae (Mbaveng et al., 2014). Antifungal fractions derived from the chloroform extract of
Artemisia annua afforded two cadinane derivatives
Mechanism of Action (arteannuin B and artemisinin), oleanolic acid, β-sitosterol,
stigmasterol. arteannuin B, a main sesquiterpenoid in A.
The main key phytochemicals to determine the reactivity annua, showed antifungal activity against one human (C.
of terpenoids are thymol and carvacrol that are abundant albicans, MIC: 100 μg/mL) and four plant pathogenic fungi
in thyme oil. Thymol normally hinders the formation and (Gaeumannomyces graminis var. tritici, Rhizoctonia
viability of hyphae and promotes morphological alterations cerealis, Gerlachia nivalis and Verticillium dahliae, MICs:
in the envelope of C. albicans. Furthermore, in a dose- 150, 100, 150 and 100 μg/mL, respectively) (Tang et al.,
dependent manner, thymol express anti-inflammatory 2000). Terpenoids isolated from sunflower have also
effects by depriving the expression of the pro- shown antifungal activities towards V. dahliae and S.
inflammatory mediators’ gene. Terpenoids also target sclerotiorum as they inhibited the hyphal growth (Picman
mitochondria resulting in significant death of S. cerevisiae, et al., 1990). Ascosteroside, ergokonin A, arundifungin,
especially in the case of lupeol. Data clearly shows that and enfumafungin were reported as novel natural
terpenoids reduced the mitochondrial content, thus products. There is a possibility to develop an oral
modified the level of reactive oxygen species (ROS) and antifungal agent by the action that inhibits (1,3)-β-D-
ATP generation. It is also reported that triterpenoid glucan synthase.
possesses more potent antifungal activity as compared to The promising antifungal properties of terpenoids were
the tetraterpenoid (Haque et al., 2016). comparable to the commercial compounds, MK-0991 and
The hydrophobic nature of terpenoid phenols allow L-733560 (antifungal agents). Moreover, the four
infusion into the lipid membrane. However, p-cymene, a terpenoids (ascosteroside, ergokonin A, arundifungin and
precursor of carvacrol, has a higher partition coefficient for enfumafungin) preferentially inhibited various pathogenic
lipid membranes; therefore, hydrophobicity alone does not Candida and Aspergillus strains. The antifungal spectrum,
ensure its antifungal action. Instead, the hydroxyl group the change in morphology, and the antagonism of
contributes to the function. The delocalized electron in antifungal activity by sorbitol, for instance, suggested that
carvacrol facilitates the dissociation of H+ from the OH terpenoids disrupted the construction of glucan fungal cell
group that resulted in H+ and monovalent cations such as wall (Onishi et al., 2000).
K+ migrate across membranes by carvacrol and eliminate
pH and K+ gradients across cell membranes. Besides, Saponins
carvacrol also depolarizes bacterial cell membranes.
However, that mechanism does not explain the transient What are saponins?
Ca2+ bursts associated with carvacrol. It might, therefore,
be that the effects on membrane expansion and fluidity Saponins are phytochemicals that produce foam (soap
that cause the opening of ion channels followed by their properties) when dissolved in water. Saponins are
rapid desensitization (Rao et al., 2010). To sum up, glycosides comprising of an aglycone (sterol or common
terpenoids may act in four ways; (1) the formation of triterpene) unit linked to one or more carbohydrate chains
hyphae (2) reducing gene expression (3) mitochondrial (sugar) as shown in Figure 3. The most common saponins
dysfunction (Ludwiczuk et al., 2017), (Haque et al., 2016) are triterpenoid saponins that contain a hydrophilic part at
and (4) depolarization of membranes and calcium ion one end separated from the lipophilic or hydrophobic part
stress (Rao et al., 2010). at the other. Steroidal saponins are normally found in the
monocotyledons. Natural sources of saponins are oats,
Antifungal activity of terpenoids asparagus, spinach, soy legumes, beans and peanuts,
and tea (Bone and Mills, 2013). The fundamental role of
Terpenoids in Cannabis have a variety of effects, such as saponins in plants is protection against the attack of
antifungal and antimalarial activity. Terpenoids from hash pathogens and pets. These molecules have high
oil obtained from drug cultivars of Cannabis displayed an commercial value that has been used as drugs, foaming
antimicrobial effect that was greater than essential oil agents, sweeteners, taste modifiers and cosmetics (Mert-
derived from fiber cultivars (Hazekamp et al., 2010). Türk, 2006).
Terpenoid phenols carvacrol, thymol, and eugenol, which
are the major components of oregano extract, have a

Saponin Medicagenic acid 3-O-beta-D-glucopyranoside
Fluconazole Tomatidine
Sapindoside B
Figure 3: Structure of saponins reported in this review. Reproduced with permission from (Tsuzuki et al., 2007).

Mechanism of Action pentosylhexoside), and oleanolic acid- hexosyl-

deoxyhexosyl-hexoside (Porsche et al., 2017).
Based on the literature, spirostanol framework and the
number of oligosaccharide residue attached at C-3 of Phenolics
aglycone appear closely associated with antifungal effects
of steroid saponins (Zhang et al., 2006). Saponins may What are phenolic compounds?
damage the cell membrane and cause cellular materials
to leach out, which ultimately leads to cell death Natural phenolic compounds are secreted by plants and
(Mshvildadze et al., 2006). For example, an antimycotic microorganisms. They are characterized by their low
saponin from alfalfa root (medicagenic acid 3-O-beta-D- molecular weight with at least one phenolic group. They
glucopyranoside), formed stable complexes with are the secondary metabolites produced by the plant
ergosterol, which resulted in lethal leakage of ions out of within their ordinary development and they are
the yeast cells (Polacheck et al., 1991). The cell reproduced as well under pressure conditions, for
membrane of C. albicans was severely destroyed by example, ultraviolet and incision (Shi et al., 2003).
fluconazole (saponin) from Tribulus terrestris L (Zhang et Phenolic compounds are standout amongst the most
al., 2006). Tea polyphenols (TP) and tea saponin (TS) and famous phytochemicals; they are of extensively
their combination were investigated against Rhizopus significant in terms of physiology and morphology in
stolonifer. The two compounds significantly induced the plants. These compounds assume a vital job in
production of H2O2, leading to membrane lipid development and generation, giving insurance against
peroxidation, which resulted in increment of the cell pathogens and predators, other than contributing
membrane permeability and leakage of soluble sugar, towards the taste and the color of the plant fruits. These
soluble protein and K+. Saponins have also destroyed the compounds are derived from the pentose phosphate,
structure of the hyphal cell. It is concluded that TP, TS shikimate, and phenylpropanoid tracks in plants
and their combination inhibited the R. stolonifer growth (Balasundram et al., 2006). Phenolic acids, flavonoids,
through inducing the production of H2O2, resulting in the tannins, stilbenes, curcuminoids, coumarins, lignans,
oxidative damage of the cell membrane and leakage of quinines and so forth are phenolic compounds isolated
intracellular materials (Jiang et al., 2015). The antifungal from the herbs of medical benefits and dietary plants
and antiparasitic activities of tomatidine (a saponin (Huang et al., 2009).
produced by tomato; Solanum lycopersicum) against
Saccharomyces cerevisiae and some parasites, such as Mechanism of Action
Leishmania amazonensis and Phytomonas serpens, have
been reported. It was revealed that tomatidine induced a One of the proposed mechanisms for antifungal agents is
perturbation of ergosterol biosynthesis through the their binding to membrane ergosterol. To determine
inhibition of Erg6 (C-24 sterol methyltransferase) activity whether the phenolic extract of ethyl acetate fraction from
and Erg4 (C-24 sterol reductase) activity (Dorsaz et al., Cochlospermum regium (mart. Et. Schr.) Pilger roots bind
2017). to the fungal membrane sterol, the MIC was determined
with and without the addition of exogenous ergosterol.
Antifungal activity of saponin MICs values will be higher with the addition of fungal
sterol if the activity was caused by binding to ergosterol.
Saponin extract from rhizomes of Dioscorea panthaica An increase at MIC of Candida krusei was induced, but no
Prain et Burk (Huangshanyao saponin extract, HSE) was change was detected with C. glabrata, C. albicans and C.
tested against C. albicans. HSE inhibits the planktonic tropicalis. This is a piece of evidence of the binding of this
growth and biofilm formation and development of C. phenolic compound to the membrane (Carvalho et al.,
albicans at a concentration of 16–64 µg/mL. Furthermore, 2018). Two mechanisms could be involved in this process:
inhibitory activities against extracellular exopolysaccharide (i) binding to membrane ergosterol forming pores in this
(EPS) production and ROS production in preformed structure (Campoy and Adrio, 2017), or (ii) inhibition of
biofilms could be inhibited by 64–256 µg/mL of HSE. enzymes involved in the synthesis of ergosterol, which
Cytotoxicity against human was also tested with Chang’s reduces the content of that macromolecule (Ahmad et al.,
liver cells, but the cytotoxicity was low with a half-maximal 2015). Phenolic acids, such as ferulic and gallic acids, are
inhibitory concentration (IC50) of about 256 µg/mL (Yang known to affect the cell membrane of bacteria, which
et al., 2018). results in changes in the hydrophobicity and charge of the
The antifungal activity of Sapindus mukorossi extract cell surface, causing leakage of cytoplasmic content
was tested against Venturia inaequalis and Botrytis (Borges et al., 2013). A similar effect has been proposed
cinerea – two important fungal pathogens worldwide. The for the caffeic acid derivatives on Candida cytoplasmatic
spray extract with a concentration of (1% v/v) significantly membrane. Mode of action of several phenolic
reduced V. inaequalis symptoms and sporulation (99%) compounds have provided some clues to infer the
on apple seedling leaves (P ≤ 0.05). The applications of mechanism of phenolic acids. For instance, curcumin,
1% v/v of the extract reduced the disease severity of B. isoquercetin and lariciresinol can damage the C. albicans
cinerea on grapes on average by 63%. The saponins cell membrane. However, methyleugenol and eugenol
identified were sapindoside B (hederagenin- significantly reduced the biosynthesis of ergosterol in

Candida and thus, affected the cell membrane (Ahmad et albicans after treatment with caffeic acid, rosmarinic acid
al., 2015). Few studies have explained about other and apigenin (Cheah et al., 2014), (Figure 4 and Figure
possible pathways of phenolic acid mechanism against 5).
Candida. For instance, isocitrate lyase was inhibited in C.
Figure 4: Tricarboxylic acid (TCA) cycle (black arrows) and glyoxylate cycle (dashed arrows). Adapted from Cheah HL,
Lim V, Sandai D (2014), PLOS ONE 9(4): e95951. Creative Commons Attribution License.
Catechin Luteolin

Quercetin Gallic acid
Baicalein Wogonin
Ferulic acid Caffeic acid
Curcumin Isoquercetin

Lariciresinol Methyleugenol
Eugenol Rosmarinic acid
Apigenin
Figure 5: Structures of phenolic compounds reported in this review.

Antifungal activity of phenolic compounds and antiHIV, coumarins have shown a strong antifungal
activity (Montagner et al., 2008).
Several studies have been performed in order to Coumarins are classified based on their structural
evaluate the antifungal potential of polar extracts from diversity into four groups. Coumarin derivatives or
plant origin, which are enriched in phenolic compounds, called simple coumarins, consist of two rings and
such as aqueous, ethanolic, methanolic, hydroalcoholic, substituted on their C7, C6 and C3 positions by
acetone and dimethyl sulfoxide (DMSO). The most benzopyrone, hydroxyl, methoxy and aliphatic groups.
studied preparations are the aqueous extracts, followed The second group of coumarins is isocoumarin
by methanolic and ethanolic extracts (Martins et al., derivatives, formed by benzene rings and α-isopirone
2015). The aqueous phenolic extract from Fragaria and they have substituents in positions C3, C6, C7 and
virginiana Duchesne, Epilobium angustifolium L. and C8. They are isolated mainly from fungi: Artemisia,
Potentilla simplex Michx. demonstrated strong Aspergillus, Fusarium, Penicillium, Streptomyces and
antifungal potential. Fragaria virginiana had some the few plants belonging to families: Compositae,
degree of activity against all of the fungal pathogens; Leguminosae and Myrtaceae. The third group is
Alnus viridis DC., Betula alleghaniensis Britt. and furanocoumarin derivatives, consist of coumarin ring
Solidago gigantea Ait. (Webster et al., 2008). Alves et coupled with the furan ring at the C6-C7 position
al. (2014) evaluated the antifungal effect of catechin, (psoralen type) or in the C7-C8 position (angelicin type).
luteolin, quercetin, and gallic acid, phenolic compounds Finally, the fourth group is pyrancoumarin derivatives,
identified from flowers of North-Eastern Portugal, where the coumarin ring is condensed with pyran ring to
against Candida planktonic and biofilm cells. MIC form xanthyletin-type if the condensation is at the C6-
values demonstrated that gallic acid presented the C7 position, or seselin-type if at the position C7-C8
highest effect against all Candida species. Catechin (Tomasz Kubrak et al., 2017).
showed a similar effect against C. albicans American
Type Culture Collection (ATCC) 90028 cells. In addition, Antifungal Activity of Coumarins
gallic acid and quercetin had demonstrated only a
minimal effect against Candida species biofilms (Alves Osthole is a coumarin isolated from plants with
et al., 2014). Zabka and Pavela tested the antifungal therapeutic capacities like Angelica pubescens,
efficacy of 21 phenolic components of essential oils and Cnidium monnieri, and Peucedanum ostruthium.
plant substances against these filamentous fungi; Rhizoctonia solani, Phytophtora capsici, Botrytis
Fusarium, Aspergillus and Penicillium genera. Thymol cinerea, Sclerotinia sclerotiorum, and Fusarium
and carvacrol were evaluated as the most effective. The graminearum are highly pathogenic fungi and osthole is
MIC₅₀ values for thymol ranged from 30 to 52 μg/mL. used as a treatment against them due to its high
The MIC₁₀₀ values for thymol ranged from 76 to 255 antifungal activity spectrum. Psoralen, imperatorin, and
μg/mL, respectively. For carvacrol, the MIC₅₀ values ostruthin have the highest antifungal effectiveness of all
ranged from 37 to 76 μg/mL, and the MIC100 ranged the coumarins (Venugopala et al., 2013). In addition to
from 131 to 262 μg/mL (Zabka and Pavela, 2013). the examples cited in Table 1, byosthol is a derivative of
Fungal culture in the presence of various concentrations coumarin isolated from celery plants, which
of baicalein extracted from Ou-gon extracts showed demonstrates activity against R. solani, P. capsici, B.
antifungal activity against T. rubrum, Trichophyton cinerea, S. sclerotiorum and F. graminearum (Tomasz
mentagrophytes, Aspergillus fumigatus, and Candida Kubrak et al., 2017). In Table 1, the two types of
albicans. Wogonin obtained from the same plant coumarins with antifungal activity are cited.
exhibited antifungal activity towards all fungi except C. In Srinivasan and Sarada (2012), the antifungal
albicans (Da et al., 2019). activity of pyranocoumarin (PDP) available in Psoralea
corylifolia was established. In addition to their capacity
Coumarins as an antifungal agent against Fusarium sp., the
molecular docking analysis performed with the X-ray
What is coumarins? crystal structures of Tri101, trichothecene 3-O-
acetyltransferase available in the Protein Data Bank
From their name, coumarins are derived from proposed a hypothetical mechanism for antifungal
Coumarouna odorata plant; they are one of the activity against plant pathogen Fusarium sp. The
benzopyrones which consist of benzene fused to α- minimum inhibitory concentration of 1 mg/mL was
pyrone ring. Coumarins are numerous; around one detected for the PDP against F. oxysporum, F.
thousand coumarins are present with abundance in moniliforme, and F. graminearum. The molecular
angiosperms. They are found in over 150 different docking has shown the affinity towards the target
species of plants belonging to almost 30 different protein and by binding to the protein, it will inhibit the
families. They are mainly secondary metabolites of acetylation mechanism ending by fungi death. C.
plants and present in some microbes. In addition to their albicans exposition to coumarin within twenty-four hours
activity as an antioxidant, antiinflammatory, antifilarial, has shown cell membrane and cell wall alteration, and
antiulcerogenic, trypanocidal, antibacterial, antitumor

Table 1: Most effective coumarins with antifungal activity.
Type of Chemical structure Example of coumarin Plant of origin Fungi target Reference
coumarin
Simple Ostruthin Peucedanum Saccharomyces (Feuer, 1974)
coumarins HO O O ostruthium cerevisiae
Osthole Angelica Rhizoctonia solani, (Wang et al.,

pubescens, Phytophtora capsici, 2010)
Cnidium monnieri, Botrytis cinerea,
and Sclerotinia sclerotiorum,
Peucedanum and Fusarium
ostruthium graminearum
HO O O
Furano- Imperatorin Glehnia littoralis, Saccharomyces (Kozioł and

coumarins Prangos pabularia, cerevisiae Skalicka-
Woźniak,
Clausena ansium, 2016)
and Aegle
O marmelos
O O O
Psoralen Psoralea corylifolia Fusarium oxysporum, (Srinivasan

Fusarium moniliforme, and Sarada,
O O O 2012)
and Fusarium
graminearum

cytoplasmic volume decreases followed by structural Mechanism of action

disarrangement. However, the mode of function
adopted by coumarin (1,2-benzopyrone) has yet to be The two alkaloids; liriodenine methiodide (LMT), a
depicted. Respiration and ergosterol synthesis methiodide salt of liriodenine, and eupolauridine 9591
dysfunctioning were the strategies adopted by silver (I)- (E9591), a synthetic analog of eupolauridine, exhibit
coumarin complexes against C. albicans whereby the their antifungal activities by interrupting mitochondrial
exact mechanism targeted cytochrome c synthesis iron-sulfur (Fe-S) cluster synthesis (Tripathi et al.,
disruption, which may also cause apoptosis (Srinivasan 2017). There are several studies lending support to this
and Sarada, 2012). Jia et al. (2019) have studied the theory. First, it was shown that both LMT and E9591
effects of coumarin on cell growth inhibition and strain provoked a transcriptional response indicating iron
viability reduction by experimenting and determining imbalance. This induces the genes that are needed for
yeast apoptosis with phosphatidylserine (PS) iron uptake and for the maintenance of cellular iron
externalization, DNA fragmentation, cytochrome c homeostasis. Second, the analysis of a genome-wide
release, and metacaspase activation. Their results fitness profile showed that mutant yeast cells that lack
explored the role of coumarin in PS exposure on the the iron homeostasis-related genes displayed
outer leaflet, DNA degradation and nuclear compaction, hypersensitivity to LMT and E9591. Third, introducing
cytochrome c release, and metacaspase activation, LMT and E9591 to treat wild-type yeast cells resulted in
suggesting that coumarin induced apoptosis in C. cellular defects that imitated deficiency in mitochondrial
albicans. Previous studies have demonstrated that Fe-S cluster synthesis, which include iron levels
coumarin damages C. albicans cells via pore formation increment in mitochondria, respiratory function
in the fungal cell wall and seep of cytoplasmic contents reduction, oxidative stress increment and loss of activity
and necrosis are phenomena adopted by coumarins of Fe-S cluster enzymes. Another study by Dhamgaye
and elaborated previously (Jia et al., 2019). et al. (2014) explored a plant alkaloid berberine (BER)
for its antifungal potential. They have found a heat
Alkaloids shock factor (HSF1) in TF mutant strains of C. albicans.
The mutant displayed collateral susceptibility towards
What are alkaloids? drugs targeting cell wall (CW) and ergosterol
biosynthesis and was highly susceptible to BER. The
Deriving from amino acids and with a nitrogen atom in treatment with BER of Candida cells led to dysfunctional
the heterocyclic ring, alkaloids are formed and mitochondria, proven by the slow growth in non-
considered as an important class of structurally fermentative carbon source and poor labeling with
diversified compounds. Alkaloid nomenclature is mitochondrial membrane potential sensitive probe
derived from the Arabic term al-qali, the plant from (Dhamgaye et al., 2014). In summary, the suggested
which soda was first isolated. Alkaloids cover roughly mechanism of alkaloids is causing a malfunction of the
20% of plant-based secondary metabolites and they mitochondria, which causes a direct impact on the
exhibit antimicrobial, anticancer, narcotics, toxic growth, respiratory activity and enzyme activity, hence,
substances and stimulant capacities. Nowadays, causes cell imbalance. The structures of alkaloids in
around 12,000 alkaloids are confined from various this review are shown in Figure 6.
genera of the plant kingdom. This number makes this
class of natural products biologically important (Kaur Antifungal activity of alkaloids
and Arora, 2015).
The examples of alkaloids acting as antifungal are Singh et al. (2007) tested the antifungal properties of
numerous. The mode of their antifungal action is usually allosecurinine, an alkaloid extracted from Phyllanthus
pleiotropic, where protein synthesis is inhibited, and the amarus Linn. (Family: Euphorbiaceae). The alkaloid
fungal DNA is intercalated or by boosting the inhibited mild spore germination of Curvularia lunata,
development of fungi inhibitors. The first medically Curvularia sp., Collectotrichum sp., C. musae and
useful example of an alkaloid was morphine, isolated in Heterosporium sp. at very low concentrations of
1805 from the opium poppy Papaver somniferum (Arif allosecurinine (Singh et al., 2007). The ethanolic extract
et al., 2009). Phenanthridine, an alkaloid isolated from of the leaves of Alstonia scholaris contained seven
Chelidonium majus exhibits antifungal activity against monoterpenoid indole alkaloids. The isolated
the clinical drug-resistant yeast isolates. Bis- compounds were tested in vitro the antifungal potential
benzylisoquinoline alkaloids such as cycleanine and against five species of fungi. The extract showed
cocsoline isolated from Albertisia villosa have antifungal activity against two fungal strains; Gibberella
antibacterial, antifungal, antiplasmodial activities in pulicaris and Cercospora nicotianae (Wang et al.,
addition to cytotoxic potential related to these alkaloids 2013). Six different species of Amaryllidaceae
(Kaur and Arora, 2015). generated various alkaloids, which were studied by
Miroslav et al. (2015) with respect to their anti-yeast
activity. The analysis showed 25 alkaloids with 16
identified from their retention indexes, retention times
and mass spectra. In the antimicrobial assay, isolates of

Phenanthridine Cycleanine
Cocsoline Allosecurinine
Liriodenine methiodide Eupolauridine
Berberine
Figure 6: Structures of alkaloids reported in this review.

the human pathogenic yeasts Candida albicans, C. fungus by its trans-anethole that inhibits chitin synthase
glabrata, C. dubliniensis and Lodderomyces activity in permeabilized hyphae (Yutani et al., 2011).
elongiosporus were tested. The six extracts, together Another example of cell membrane disruption is by the
with 19 Amaryllidaceae alkaloids showed promising essential oil extracted from Citrus sinensis epicarp that
anti-yeast properties although no antibacterial activity contains almost 85% limonene. This essential oil leads to
was detected. Among the alkaloidal extracts, Narcissus the irreversible deleterious morphological alteration that is
jonquilla cv. Baby Moon had the most effective anti- capable of inhibiting the growth of Aspergillus niger
yeast, with minimal and average MIC values of 128 and (Sharma and Tripathi, 2008). A similar effect is exhibited
192 µg/mL, respectively, followed by Leucojum by thymoquinone, a component of black cumin seed
aestivum, Narcissus poeticus var. recurvus and N. essential oil that extensively damages the fungal cell wall
canaliculatus (Miroslav et al., 2015). and cytoplasmic membrane (İşcan et al., 2016).
Essential oils ii. Dysfunction of fungi mitochondria
What is an essential oil? Essential oils can inhibit mitochondrial dehydrogenase

systems responsible for biosynthesis of ATP such as
Essential oils are a complex mixture of natural compounds lactate dehydrogenase, malate dehydrogenase and
obtained mainly from plants or herbs. The physical succinate dehydrogenase. For example, Anethum
properties of essential oils are they appear as a colored graveolens essential oil was capable of inhibiting Candida
mixture of several aromatic compounds, liquid and volatile albicans’s ATP biosynthesis and at the same time
(Macwan et al., 2016). The ultimate role of essential oils is disturbed the citric acid cycle (Chen et al., 2013). Other
to protect plants against any threat from the environment, essential oils that were extracted from various plants such
such as pathogens and insects that act as plug vectors. as Origanum compactum, Artemisia herba alba and
Therefore, they are well-known for their medicinal Cinnamomum camphora also shows mitochondrial
properties such as antiseptic, anti-carcinogenic, anti- damage when treated to Saccharomyces cerevisiae. The
inflammatory, analgesic, anesthetic and they are mainly antifungal activity of essential oil towards mitochondrial
used as natural additives in food and food products due to damage was comprehended to be the role of terpenoids
their antioxidant and antimicrobial properties. that give rise to an altered level of reactive oxygen
species and ATP generation (Haque et al., 2016).
Phytochemical compounds of essential oils
iii. Inhibition of Efflux pumps
The chemicals composition of essential oils is affected by
several factors such as plant species, method of The physiology of fungi such as the electrochemical
extraction, geography and environment. Different location proton gradient across the cell membrane for nutrient
has a different composition of the chemical compounds of uptake, intracellular pH, fungal growth, and fungal
essential oil due to climate differences, humidity which pathogenicity were all supported by fungal plasma
constitute different species of insect or microbial membrane H+-ATPase (Haque et al., 2016). Apart from
properties that induce the plant to produce its own that, the fungal plasma membrane also regulates nutrient
phytochemicals. Terpenes (p-cymene, limonene, uptake and medium acidification (Perlin et al., 1997).
terpinene, sabinene and α- and β-pinene) and terpenoids Therefore, inhibition of H+-ATPase leads to intracellular
(thymol, carvacrol, linalyl acetate, linalool, piperitone, acidification and cell death. Thyme oil exhibits the over-
citronellal, geraniol and menthol Figure 7) are the main expression of the efflux-pump gene. The chemical
categories of compounds in essential oil fairly at high components that play a role in the inhibition of the over-
concentration (20-70%) (Niu and Gilbert, 2004). expression of efflux-pump genes CDR1 and MDR1 in C.
albicans are thymol and carvacrol and the reaction is
Mechanisms of Action located at the membrane level (Nazzaro et al., 2017).
i. Cell membrane disruption Antifungal activities of essential oils
The fungal cell wall consists of essential elements such as The presence of fungal infection is more difficult to verify
glucan, chitin and mannan for fungal survival. and difficult to treat and eliminate as compared to
Phytochemicals in essential oils affect fungal cell wall bacterial infection. The inception and acuteness of fungal
maturation, septum formation and bud ring formation (Wu infection depend on the host’s resistance and inoculum
et al., 2008). This leads to the thinning and distortion of charge. The synthetic antimicrobial treatment of fungal
the hyphal wall, thus causing the hyphal tip to be divided infection is effective, but in the long term, it will generate
into bud-like structure. The severity of damage can be up resistant fungal species and caused side effects on the
to the level where the cytoplasm leakage inhibits DNA, organ (liver and kidney) functionality (Williams and Lewis,
RNA, protein and peptidoglycan biosynthesis and, lastly, 2011). Due to apprehension on the safety of synthetic
inhibits the ergosterol biosynthesis (Nazzaro et al., 2017). antimicrobial agents, the limelight has been diverted to the
Anise oil manifests antifungal activity against filamentous potential application of essential oil as an alternative

Terpenes
CH3
H3C CH3
p-cymene α- pinene β-pinene
Limonene Terpinene Sabinene

Terpenoid
Carvacrol Thymol Linalyl acetate
Piperitone Geraniol Linalool
Menthol Citronellal
Figure 7: Structures of terpenes and terpenoids reported in this review.

treatment for fungal infection. Essential oils have a broad List of essential oils with antifungal effect
spectrum of antifungal properties and are environmentally
friendly (no non-toxic residue and by-product). The Many essential oils are now known to contain powerful
antifungal activity of essential oil is highly due to the antifungal properties and the following list is not
existence of terpenes/terpenoid and the lipophilic exhaustive but representative of those commonly believed
properties that enable disruption of the cell wall and to be the best treatment for fungal infections and
membranes and organelles of the fungal cell and/or inhibit scientifically proven to possess antifungal qualities (Table
nuclear material or protein synthesis that leads to death of 2).
fungi (Figure 8) (Tian et al., 2011).
Figure 8: Antifungal activities of essential oils towards fungi.
Table 2: List of potential essential oil for antifungal treatment.
Name of plants Biochemical compound Antifungal activity Reference

Stems of Croton Epiglobulol, α-bisabolol, α- Candida species; C. albicans (ATCC 90028), (Huang et
tricolor trans-bergamotol and β- C. albicans (LM105), C. tropicalis (ATCC al., 2019)
caryophyllene 13,803), C. tropicalis (LM 14), C. krusei
(ATCC 6538) and C. krusei (LM 12).
Polyscias fulva Saponins, tannins, M. audouinii, T. rubrum, T. ajelloi and T. (Njateng et
alkaloids, anthraquinone equinum, T. mentagrophytes, T. terrestre, M. al., 2013)
and phenols gypseum and E. floccosum
Ferulago capillaris Limonene and α-pinene Candida, Cryptococcus, Aspergillus and (Pinto et
dermatophyte strains al., 2013)
Moringa oleifera Lam Pentacosane and T. rubrum, T. mentagrophytes, E. floccosum (Chuang et
hexacosane and M. canis al., 2007)
Allium sativum Di-2-propenyl trisulfide and T. erinacei, T. rubrum, and T. soudanense (Pyun and
di-2-propenyl disulfide Shin, 2006)
Curcuma longa Turmerone, atlantone, and T. mentagrophytes, T. rubrum, E. floccosum, (Jankasem

zingiberone and M. gypseum et al.,
2013)
Eugenia cariophyllata Eugenol C. albicans, C. tropicalis, C. krusei, T. (Gayoso et
rubrum, T. mentagrophytes and Geotrichum al., 2005)
candidum
Salvia cryptantha α-pinene, eucalyptol, C. albicans and C. krusei (Tepe et

and S. multicaulis camphor, camphene and al., 2004)
borneol

Antifungal peptides membrane and cell leakage and cell death (necrosis).
Another mode of the mechanism of action of AFP is where
What are antifungal peptides? the membrane interaction may not primarily damage the
plasma membrane, but the interaction with specific lipid or
Antifungal peptides (AFP) are small cationic, amphipathic protein components of the plasma membrane caused the
molecules with less than 50 amino acids isolated from formation of a transient pore. The interaction resulted in
plants, animals, bacteria and fungi (Matejuk et al., 2010). the protein transport into the host cell and interacted with
AFP is a cysteine-rich protein that encodes various AFP the intracellular target. This led to an increase in the
that belong to different classes (Garrigues et al., 2018). cellular level of reactive oxygen species (ROS) and
With confine requirement for commercialization, AFP triggered programmed cell death (Brogden, 2005).
prominently meets the desired criteria to be a commercial
antifungal. Firstly, it is highly stable toward high Classification and antifungal activity of peptides
temperatures, proteolysis, as well as acidic condition
(Dorsaz et al., 2017). In nature, antimicrobial and Antifungal peptides can be classified into two groups
antifungal peptides are the first-line defense for any based on their mechanism of action, which are lysis and
organism against a wide spectrum of microbe infection cell wall synthesis interference (Figure 9). Lytic peptides
that has no toxic effect towards the host organism have the characteristic of amphipathic. Amphipathic
(Matejuk et al., 2010). Evidence suggests that the molecules possess a polar and non-polar region that is
antifungal activity of antimicrobial peptides (AMPs) is hydrophilic and hydrophobic, respectively. The lytic
multifactorial. The modulation of the immune system and antifungal peptide can bind to the cell membrane and
the host immune status determine the efficacy of the disrupt the membrane structure without traversing, or it is
peptide likely similar to other antifungal agents (Ben-Ami able to traverse the cell membrane and interact with
et al., 2008). specific intracellular molecules. Some lytic peptides form
an aqueous pore allowing transposes of ions and other
Mechanism of action solutes (De Lucca and Walsh, 1999).
Initial effort to commercialize antimicrobial peptides
There are two modes of the mechanism of action of AFP; (AMP) was unsuccessful due to the complex biology and
the first one is through permeabilization of the cell pleiotropic nature of AMP that was not fully understood
membrane, which may break down into two mode of (Duncan and O’Neil, 2013). Another difficulty for the
actions. The first one is the carpet model, where protein commercialization of AMP is their biological instability.
molecules insert into the membrane and forming pores. AMP is more susceptible to proteolytic degradation in the
The second one is the pore model, where the protein systemic environment that resulted in a shorter half-life of
molecules oligomerize and form a multimeric pore AMP, thus making it unable to maintain plasma
(Brogden, 2005). Both models are based on AFP bacterial concentration needed for their minimal inhibitory
interaction, where the cationic character of defensins concentration (Duncan and O’Neil, 2013). There is a need
interacts with the negatively charged plasma membrane of to develop AMP molecules that retain their positive
bacteria. What follows is the disintegration of the plasma
Figure 9: Classification of antifungal peptides.

physiochemical functions but devoid of the negative CONFLICT OF INTEREST

features such as hemolytic and inflammatory potential that
previously held back their translation into the clinical stage Authors declare no conflict of interest in this project.
(Ahmad et al., 1995). The ability to kill yeast, hyphae,
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Phytochemicals with antifungal properties: Cure from nature

Article · June 2020

Amal Ahmed Elgharbawy Nurhusna Samsudin

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Yumi Zuhanis Has-Yun Hashim Farah Fadwa Ben belgacem

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Malaysian Journal of Microbiology

Phytochemicals with antifungal properties: Cure from nature

Aziz, 50300 Kuala Lumpur, Malaysia.

INTRODUCTION Chaetomium and Stachybotrys (Baxi et al., 2016) and few

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Sesquiterpenes Triterpinoid Oleanolic acid

Warburganal Muzigadial Thymol

CH3 CH3 CH3

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Saponin Medicagenic acid 3-O-beta-D-glucopyranoside

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Mechanism of Action pentosylhexoside), and oleanolic acid- hexosyl-

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Quercetin Gallic acid

Ferulic acid Caffeic acid

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Eugenol Rosmarinic acid

Figure 5: Structures of phenolic compounds reported in this review.

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Table 1: Most effective coumarins with antifungal activity.

Osthole Angelica Rhizoctonia solani, (Wang et al.,

Furano- Imperatorin Glehnia littoralis, Saccharomyces (Kozioł and

Psoralen Psoralea corylifolia Fusarium oxysporum, (Srinivasan

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cytoplasmic volume decreases followed by structural Mechanism of action

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Liriodenine methiodide Eupolauridine

Figure 6: Structures of alkaloids reported in this review.

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Essential oils ii. Dysfunction of fungi mitochondria

What is an essential oil? Essential oils can inhibit mitochondrial dehydrogenase

i. Cell membrane disruption Antifungal activities of essential oils

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p-cymene α- pinene β-pinene

Limonene Terpinene Sabinene

Carvacrol Thymol Linalyl acetate

Piperitone Geraniol Linalool

Figure 7: Structures of terpenes and terpenoids reported in this review.

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Figure 8: Antifungal activities of essential oils towards fungi.

Table 2: List of potential essential oil for antifungal treatment.

Name of plants Biochemical compound Antifungal activity Reference

Curcuma longa Turmerone, atlantone, and T. mentagrophytes, T. rubrum, E. floccosum, (Jankasem

Salvia cryptantha α-pinene, eucalyptol, C. albicans and C. krusei (Tepe et