Antifungal Activity of Propolis against *Candida* Species: Propolis and Antifungal Action

*Emine Kucukates*

#### **Abstract**

*Candida* species live as commensal in humans and cause candidiasis in the presence of some predisposing factors. They are the most common among systemic mycosis agents. Currently, existing drugs used in the treatment of *Candida* infections may develop resistance, especially azole group compounds, and may lead to serious side effects and problems that may occur in therapy. Therefore, alternative natural treatment methods with very low side effects or no side effects should be considered. Propolis is one of the most natural products which has been used as a natural drug in traditional medicine for the treatment of various diseases for thousands of years. Propolis is a sticky resinous substance collected and deposited by bees from plant buds, leaves, and stems. Propolis has a wide spectrum of biological activities such as antibacterial, antifungal, antiviral, antiparasitic, anti-inflammatory, immunomodulatory, and antioxidant. The compounds responsible for the biological activity of propolis are thought to be flavonoids, caffeic acid and esters, phenolic compounds, aromatic acid and esters. In this chapter, I aimed to investigate the antifungal activity of propolis against *Candida* species. Considering the safety, low cost, and usefulness of propolis, it should be considered as an alternative natural treatment method.

**Keywords:** propolis, antifungal activity, *Candida* species

### **1. Introduction**

#### **1.1** *Candida* **species**

*Candida* species are diploid, dimorphic, asexual fungi, and common in nature and humans and they live harmless, commensal in humans [1]. Yeasts of the genus *Candida* are found in the skin, respiratory system, genito-urinary system, and gastrointestinal tract mucous membranes of humans. Although there are approximately 200 *Candida* species, at least 30 species have been identified as infectious agents in humans and continue to increase in three decades and the notional numbers of nonalbicans *Candida* infections have increased. *Candida albicans* is the most frequently isolated from *Candida* infections, followed by *Candida glabrata*, *Candida parapsilosis*, *Candida tropicalis*, *Candida krusei*, *Candida lusitanie*, *Candida dubliniensis*, and

*Candida guilliermondii* and several other less often obtained species. This genus is the largest in which medically important yeasts are found [1–4]. When the body's normal microbiota or immunity is impaired, overgrowth of *Candida* species can cause host damage and opportunistic infection may occur [5, 6]. The disease caused by *Candida* is called candidiasis. *Candida* infections can be acute, chronic, localized, or systemic. These opportunistic pathogens are a major cause of morbidity and mortality worldwide, and therefore, poses a great threat to public health [3, 4]. Risk factors for *Candida* infections are broad-spectrum antibiotic use, advanced age, *Candida* colonization in the oral mucosa, burn, malignancy, central venous catheter, steroid use, total parenteral nutrition, prosthetic devices, HIV/AIDS patients, diabetes mellitus, indwelling devices, hyperalimentation fluids, organ transplantation, immunosuppressive drugs, hemodialysis, surgical interventions, and invasive applications [1,4–7]. *Candida* species was declared to be the fourth in 2004 and third in 2014 in the United States as the most common cause of bloodstream infections (BSIs). Most of these BSIs are caused by foreign body (implant) such as catheters (peritoneal dialysis or hemodialysis, and/or intravascular catheters; central lines, arterial catheters, or peripheral intravenous catheters), prosthetic valve, endotracheal tube and joint prosthesis [3, 8–10]. Oropharyngeal candidiasis is the most common oral evidence in HIV patients. It is also common in patients with head and neck cancer [5, 11].

#### **1.2** *Candida* **virulence factors**

The virulence factors of *Candida* species declerated, to cause infections based on the site of infection, the type of infection, the stage of infection, and the host reply. The primary virulence factors of *Candida* species are biofilm formation, production of acid proteinase, phospholipases, and lipases, the ability to change its morphology from yeast to hyphal forms, and its metabolic adaptability [1, 3–12]. *Candida* first attaches to the host cells with adhesins on the surfaces of fungal cells. They have to invade the host after adherence. Many *Candida* species can form biofilm. Biofilm formation of *Candida* includes first the reproduction of yeasts on a surface contact to host cells or biomaterial, and then these are followed by filamentation. Biofilms consist of a community of microorganisms that adhere to a living or biomaterial surface, embedded in the organic exopolysaccharide matrix, they produce, and irreversibly attached to each other, to one another, to a solid surface or to an interface, and biofilms are important for the development of infection. Biofilm-forming *Candida* species can occur with conditions that clinicians do not want to encounter, such as antifungal resistance, chronic infection, and foreign body infections. Biofilmassociated *Candida* infections are very difficult to treat. The biofilm production is related to the antifungal resistance of *Candida* species [1, 4, 5, 10, 13].

#### **1.3 Antimicrobial resistance of** *Candida* **species**

Antimicrobial resistance is a threat worldwide and is a major public health problem. Antifungal selection is very important in several fungal infections, because in universal treatment, various problems such as side effects, drug interaction and toxicity, and antifungal resistance such as azole and polygenic derivatives may occur related to conventional treatments. The rapidly increasing antimicrobial resistance in the world results in an increase in the number of diseases and deaths [5, 7, 9, 13]. Therefore, alternative treatment methods with natural products due to very low side effects or no side effects should be considered. In recent years, the increase in

antimicrobial resistance and its side effects and the increase in cancer cases have led scientists to seek alternative natural treatments in modern medicine.

#### **2. Apitherapy**

Bee products have been used for treatment in folk medicine for centuries. Apitherapy is a type of alternative therapy that bee products are used that obtained directly from honeybees. Bee products such as honey, royal jelly, beeswax, bee venom, propolis, and pollen are thought to be beneficial to humans due to their biological and pharmacological properties [14–16]. It has been used all over the world, especially in China, Japan, and Korea in recent years. Apitherapy has been used for thousands of years. Bee venom therapy used since ancient times in Egypt, Greek, China, and Central Asia for various types of pain and arthritis pain and it is anti-inflammatory and helps relieve pain. Clinical studies have shown that bee venom treatment reduces the need for medication and reduces the risk of pain and recurrence. Diseases such as infections, wounds, burn, lupus, arthritis, shingles, pain, and muscle and joint disorders are some of the areas of apitherapy [16, 17]. Modern herbalists recommend propolis for the treatment of gastrointestinal ulcers and to increase the body's natural defense mechanisms against infections due to its antibacterial, antifungal, antiviral, anti-inflammatory, and liver protective properties [16]. Today, there are extensive apitherapy centers in China, Romania, and some Eastern European countries where diseases are treated with bee products [16]. With the regulation on traditional and complementary medicine practices published in 2014, in Turkey, apitherapy courses have been organized and apitherapy centers have begun to be established.

#### **3. Biological properties of propolis**

Propolis is a useful and versatile natural, non-toxic, low-cost bee product that has been used to cure diseases, and only bees can make propolis. It is used in ancient times in Egypt, Greece, Rome, Europe, and North Africa in the treatment of various diseases or to reduce their side effects. The Greeks used propolis as an antiseptic and in wound healing, while the Assyrians used it in wound and tumor treatments. Egyptians used propolis to mummify the dead [16, 18]. Propolis in Greek "pro" means "in defense for" and "polis" means "city" [19]. Propolis is a resinous and waxy substance collected by bees from the leaves, stems, buds, and similar parts of plants, which has a nice and pungent smell and does not dissolve in water. Propolis wax at 15−20° C, at 30−40° C sticky and gum-like. Generally, it melts at 60–70°C, when frozen times take a hard and brittle structure. Propolis gains a strong and sticky property due to the change of the structure of the collected plant resin by the bees [17, 18]. It is extremely rich in antioxidant content. Bees use propolis as an agent with antibacterial, antiviral, and antifungal activities to maintain a sterile environment in the hive and to protect the health of bees. Bee propolis is used the coat the inside of the hive, close the cracks, harden and repair the edges of the honeycombs, make the hive entrance hole easily defendable, and clean and polish the cells before the queen lays her eggs. It is brittle and hard in the cold but can become sticky when in hot environment. The structure of propolis consists of 50% resin and herbal balm, 30% wax, 10% essential and aromatic oils, 5% pollen, 5% protein, and other substances [19–23] (**Figure 1**). There are more than 300 compounds in the content of propolis.

These are polyphenols (flavonoids, phenolic acid, and its esters), terpenoids, steroids, aromatic acid, and its esters, alcohols, aldehydes, chalcones, hydrocarbons, quinones, amino acids, coumarin, ketones, essential fatty acids, vitamins (B1, B2, B6, A, C, and E), and minerals (calcium, magnesium, potassium, sodium, manganese, selenium, iron, zinc, and copper). Polyphenols and terpenoids are considered the most active compounds. The flavonoids are antimicrobial effect, and they include chrysin, pinocembrin, apigenin, galangin, pinostrobin, quercetin, kaempferol, tectochrysin, and other similarly structured compounds. The beneficial feature of propolis is usually due to the flavonoid groups it contains [19, 20, 23–25]. Flavonoids are generally found in photosynthesizing cells. Since they are secondary plant metabolites and cannot be synthesized by humans, they are important for human nutrition. Aromatic acids are among the other important components of propolis, and the most important ones are caffeic acid, cinnamic acid, ferulic acid, benzoic acid, and coumaric acid [24, 25]. Propolis has different and richer content than bee pollen. Propolis supports the immune system with its antimicrobial, anti-inflammatory, and antioxidant properties [23]. Propolis can be protective against tumor formation by preventing the structural change of the cell by neutralizing free oxygen radicals with its antioxidant property in cellular damages caused by oxidant. The effects on the cardiovascular system and eye health are also based on this feature [26–29]. Cinnamic acid and its active ingredients, galangin, pinocembrin, and cumaric acid in propolis are involved in a wide therapeutic spectrum. It shows antimicrobial, antifungal, and antibacterial effects [30–32]. Propolis and its extracts have numerous procedures in treating various diseases due to its antiseptic, antibacterial, antifungal, antiviral, antiparasitic, antioxidant, anti-inflammatory, antitumor, antiulcer, anticancer, scar-forming, tissue regeneration, local anesthetic, immunomodulatory and cytostatic activity. Therefore, it has been used in foods and beverages for the prevention of cancer, heart diseases, and diabetes [19, 20, 23, 33]. There are also harmful effects of propolis besides the

**Figure 1.** *The structure of propolis.*

*Antifungal Activity of Propolis against* Candida *Species: Propolis and Antifungal Action DOI: http://dx.doi.org/10.5772/intechopen.107172*

beneficial effects. Sensitive as a result of allergic reactions in humans occurring in different parts of the body such as mouth, tongue, hand, back, feet such as eczema, dermatitis (skin crusting, watery picking, itching, pain, etc.) cough, etc. symptoms can be seen [18, 27].

The structure of propolis varies according to the type of plant it is collected from, the way it is collected and used by the bee, and the methods used. Propolis should not be consumed as it is produced in the hive. Since raw propolis contains unwanted parts such as bee dead, larval remains, and plant parts, it is pre-purified by extraction with suitable solvents before use. In order for people to benefit from this product, it must be processed. Since it is a natural product and has a characteristic smell [19].

Since the chemical structure of propolis changes according to the plant source from which it is collected, different plant species can be propolis sources. Particularly in continental climate regions, mainly Populus spp., Abies spp., Acer spp., Alnus spp., Ulmus spp., Tilia spp., Pinus spp., Betula spp., Salix spp., Corylus spp., *Castanea sativa*, Eucalyptus spp., Quercus spp., and Prunus spp. are shown as botanical sources of propolis [17]. Properties such as the content, color, and smell of propolis may differ according to the vegetation around the hive, climate, season, geographical region, collection time and the source plant obtained. At the same time, these factors also affect the color of propolis. Propolis that is usually dark brown can be yellow, green, red, or transparent if these properties change. But the basic composition ratios are similar to each other [34]. However, it is reported that the season of harvesting in the same region does not have a significant effect on the composition of propolis [34].

#### **4. Collection time of propolis**

The best time to harvest propolis from the hives is between September and October. Because before the bees enter the winter months, the market holes in the hive should be as small as possible with the help of propolis in order to protect themselves in the best way possible, and they are harvested by beekeepers when the time comes. It is reported that propolis production may be more active with the onset of the rainy season in tropical climates. Phenolic compounds containing flavonoid and cinnamic acid derivatives are predominantly found in propolis obtained from temperate regions. While diterpenes and prenylated compounds are very rare in temperate zone propolis, it has been reported that they are found together with lignans, flavonoids, and other group compounds in tropical propolises obtained from South America [27].

#### **4.1 Extraction methods of propolis**

The composition of the propolis varies according to the type of solvent used and the extraction method. Solvents that do not pose a threat to health should be used in propolis extracts offered for human consumption. There may be variations in the biological effects of different solvents depending on the solubility properties of different components in propolis [35, 36]. Ethanol is the most preferred propolis extract, besides water, methanol, glycerol, methylene chloride, hexane, acetone, olive oil, and propylene glycol are other preferred solvents for the extraction of propolis. One of the solvents in the legislation, water is not preferred because it cannot dissolve the components in propolis sufficiently. Solubility in water-based propolis is only 1%. Like the tween used to dissolve chemicals with detergent, properties are harmful to health. In the case of using water as a solvent, the expected benefits cannot be

achieved due to the low rate of penetration of caffeic acid, phenyl ester, and some important flavonoids (chrysin, galangin, pinobanksin, pinocembrin) in the content. Ethanol, glycerol, and propylene glycol alcohol- derived solvents. The reason why ethanol is mostly preferred in propolis extraction is that it dissolves more bioactive substances. High-pressure liquid chromatography (HPLC) with a diode array detector (DAD) (HPLC-DAD), gas chromatography-mass spectrometry (GC-MS), liquid chromatography-mass spectrometry (LC-MS), liquid chromatography-tandem mass spectrometry (LC-MS/MS), and many chromatographic methods are used to examine the chemical structure of propolis. It is reported that HPLC-DAD and high-pressure liquid chromatography-mass spectrometry (HPLC-MS) give good results due to the polar nature of propolis (the molecular structure generally contains in OH− groups) [17, 35, 36]. Therefore, when interpreting the results of the studies, which solvent is used should be considered.

#### **5. Studies on the chemical composition and antimicrobial activity of propolis in the world**

There are many studies on the chemical structure and antimicrobial effect of propolis in the world [21, 23–29, 33–35, 37–53] (**Table 1**). Popova et al. [21] searched 114 propolis specimens from different countries to determine the chemical characteristics of poplar propolis and formed two groups according to the data obtained. Central and Southern Europe, Turkey, Syria, and other locations in continental climate (97 samples) first group, in the same zone as colder regions (Northern and mountains regions; Baltic Countries, England, Ukraine, Siberia, Canada, and Sweden) the second group. Groups varied considerably in phenolic and flavonoid content. Northern and mountainous region propolises were found to have lower values of 25% phenolic, 38% flavone and flavonol, and 17% flavonone/dihydroflavonol compared with the first group propolis. However, no significant differences were observed between the antimicrobial activities of all specimens. AL-Ani et al. [23] studied the chemical components, biological activities, and synergistic effects of antibiotics in different plant-derived propolis samples collected from various regions of Europe; Ireland, Germany, and Czech Republic. The chemical components of the ethanol extract of propolis (EEP) and water extract of propolis (WEP) were analyzed by gas liquid chromatography-mass spectrometry (GLC-MS) and high-performance liquid chromatography (HPLC), and more than 100 different phytochemicals were obtained from the ethanol and water extracts. In Irish propolis identified many flavonoids like pinocembrin, chrysin, and galangin were as well as significant amounts of nonacosane, heptacosane, pentacosane, guaiol, alpha-bisabolol, and caffeic acid. German propolis contained several acids such as benzoic acid, cinnamic acid, salicylic acid, myristic acid, 4-methoxyphenyl propanoic acid, hexadecanoic acid, and dodecanoic acid. Also, in Czech propolis detected as dominant compounds flavonoids such as galangin, pinocembrin, and chrysin and phenyl carboxylic acids such as benzoic acid, caffeic acid, cinnamic acid, and *p*-coumaric acid. All ethanol extracts displayed a free radical scavenging effect (IC50 ranging between 26.45 ± 3.4 μg/mL and 36.40 ± 3.2 μg/mL). Irish and Czech Republic propolises showed the highest free radical scavenging effect (IC50 26.45 ± 3.8 μg/mL and 27.72 ± 5.2 μg/mL). Also, water extract of propolis samples demonstrated moderately antioxidant activity (IC50 36.40 ± 3.2 μg/mL). In the investigation of antimicrobial effect, Irish propolis displayed noteworthy antimicrobial activity against

*Antifungal Activity of Propolis against* Candida *Species: Propolis and Antifungal Action DOI: http://dx.doi.org/10.5772/intechopen.107172*


#### **Table 1.**

*Chemical characterization and antimicrobial activity of propolis in the world.*

Gram-positive bacteria, the other Czech and German propolis extracts. All propolis specimens observed antifungal effects on reference and *Candida* species obtained from clinics. Excellent fungicidal effect was observed in Irish and Czech ethanol extracts with a minimum fungicidal concentration between 0.1 μg/mL and 2.5 μg/mL, also, the other propolis origins displayed mostly fungistatic effect; MIC values between 0.6–5 μg/mL. *C. tropicalis*, *Candida glabrata* and *C. parapsilosis* were the most susceptible *Candida* species. Synergism was determined in the combination of ethanol extract of propolis and vancomycin on *Streptococcus pyogenes*. Furthermore, combination of EEP and levofloxacin was found on *Streptococcus pneumoniae* and *Haemophilus influenzae*. Hegazi et al. [33] researched the chemical properties and antimicrobial effects of three propolis specimens collected from Germany, France, and Austria by GC–MS method. The main plant sources of all of these propolises were poplar buds. Flavonoids and phenolic esters were similar in all the propolises samples, but the flavonoid and phenolic ester amounts of German and French propolises were higher than that of Austrian propolis. A total of 41 components were isolated from these propolises, 11 of which defined for the first time. In the specimens searched in this study, few polar compounds were found that are characteristics of poplar buds. Compounds like aromatic acid found in all researched specimens are in the first group. *Trans-p-* coumaric was the greatest in all samples. In German propolis, galangin, benzylferulate, and phenylethyl-*trans*-caffeate were dominant. Benzyl caffeate was dominant in the French propolis specimen. Also, in French and Austrian propolis was dominant, and pinocembrin and *trans-p*-cumaric acid were dominant in all specimens. Among the studied propolises, German propolis had the highest antimicrobial effect on *S. aureus* and *E. Coli*, also Austrian propolis displayed the highest effect to *C. albicans*. French propolis was demonstrated less effective studied on all pathogens than German and Austrian propolis. Popova et al. [37] investigated the composition and antimicrobial effect of propolis specimens from six different regions of Turkey (Adana, Artvin, Erzurum, İzmir, Kayseri and Yozgat). They detected that Western (İzmir) and Central (Kayseri and Yozgat) Anatolia propolis specimens showed very similar phenolic and flavonoid ingredient. They found low phenolic and very low flavonoid concentrations in propolis samples from Adana (Central Anatolia), Artvin and Erzurum (Eastern Anatolia). Velikova et al. [38] performed a chemical analysis of a Bulgarian and two Turkish propolis types by using GC–MS. The chemical components of the propolis of both countries were similar. They reported that they probably showed the characteristics of poplar propolis. The samples were found particularly rich in caffeic acid and ferulic acids and also, they showed antibacterial, antifungal, and cytotoxic effects. Mohammadzadeh et al. [39] analyzed the chemical components of propolis collected from Tehran by GC–MS method and it has been reported that the botanical source of Iranian propolis may be popular due to the presence of acetate, pinocembrin, pinobanksin, pinobanksin-3, pinostrobin flavonones and flavones such as galangin and chrysin. Yaghoubi et al. [40] investigated the antimicrobial activity of ethanol extract of Iranian propolis (EEP) against Grampositive, Gram-negative, and fungi by disc diffusion method. EEP was only Grampositive and fungi but, not Gram-negative. They identified pinocembrin, caffeic acid, kaempferol, phenethyl caffeate, chrysin, and galangin in Iran propolis. The total phenolic and flavonoid ingredients were 36% and 7.3%. They suggested that the powerful antimicrobial effect of Iranian propolis may be due to rich sources of flavonoid and phenolic composites. Gharib et al. [41] analyzed antimicrobial effect of propolis on some bacteria and fungi. Egyptian propolis was higher effective *S. aureus* than *E. coli.* They found high antifungal effect on tested fungi. Chamandi et al. [42]

#### *Antifungal Activity of Propolis against* Candida *Species: Propolis and Antifungal Action DOI: http://dx.doi.org/10.5772/intechopen.107172*

searched the antimicrobial effect of propolis obtained from different regions of Lebanon. These microorganisms are multi-drug resistant bacteria (MDR), Extended Spectrum Beta Lactamases (ESBL) positive *Klebsiella pneumoniae*, *Methicillin Resistant S. aureus* (MRSA), and *C. albicans*. Ethanol Extract Propolis (EEP) specimens against ESBL-positive *K. pneumoniae* and MRSA displayed bacteriostatic activity. Also, it showed fungicidal effect against *C. albicans*. Moncla et al. [43] examined chemical content and antibacterial activity of Brazilian propolis against *Enterococcus* spp. They found flavonoids, prenylated compounds, and cinnamic acid derivatives as the main constituents in Brazil propolis. Kumazawa et al. [44] studied the structure of Uruguayan propolis. They found 33 compounds that are 18 flavonoids including two new compounds, 11 phenolic acid esters including one new compound, and four aromatic carboxylic acids. Components obtained from Uruguayan propolis were similar to propolis of European and Chinese origin. They suggested that Uruguayan propolis has a plant origin and is similar to those of propolis from Europe and China. Hamasaka et al. [45] investigated the chemical compositions and antioxidant activity of propolis collected from various regions of Japan (Tokyo, Nagano, Okinawa, Okayama, Tottori, Kanagawa, Akita, Fukushima, Gifu, Fukuoka, Shizuoka, and Hokkaido). They detected that the components and quantitative values of propolis vary according to geographic origin. Ethanol Extract Propolis (EEP) from Akita (Minamiakita) and Okinawa was almost potent antioxidant activity and connected with total polyphenol ingredient. Also, in propolis collected from Akita (Minamiakita) was found a large amount of antioxidant components.

#### **5.1 Studies on the chemical analysis and antimicrobial activity of propolis in Turkey**

Numerous studies are carried out on the chemical composition and antimicrobial activity of propolises produced in Turkey [15, 30, 32, 36, 54–64] (**Table 2**). Bayram et al. [15] investigated the chemical analysis and antimicrobial action of propolis from Hakkari region (Eastern Anatolia) of Turkey on some pathogens by GC–MS. They detected more the total flavonoid amount than the other compounds such as terpenes, ketones, alcohols, hydrocarbons, aromatic acids, cinnamic acids, and their esters and aliphatic acids and esters. They found pinocembrin (9.16%), pinostrobin chalcone (8.85%), ethyl oleate (8.15%), and chrysin (5.82%) as major flavonoids. Kartal et al. [54] investigated the antimicrobial activities of propolis samples collected from Ankara (Kazan) and Muğla (Marmaris) regions of Turkey, by GC–MS chromatography method and detected 24 different compounds in the samples. They prepared four different ethanol extracts (using 30%, 50%, 70%, and 96%) from propolis samples and examined the effects of these extracts on seven Gram-positive, four Gramnegative, and fungal culture. They stated that the samples taken from Ankara-Kazan showed stronger antimicrobial activity compared with the Muğla-Marmaris samples, and they stated that the chemical content of Ankara-Kazan propolis was similar to the bud secretions of Populus species. They explained that the observed activity was mostly due to caffeic acid and its esters. Also, the active components of the Mugla-Marmaris samples were determined as isopimaric acid. The other study on the chemical content of Turkish propolis was conducted by Sorkun et al. [55] and in this study, samples from different regions of Turkey (Bursa, Erzurum-Askale, Gumushanesogutagil and Trabzon-Caglayan) were collected and their chemical analyzes were performed by GC–MS. According to the results of this study, propolis samples taken from Trabzon and Gumushane regions have similar chemical content, and the basic


#### **Table 2.**

*Chemical structure and antimicrobial efficiency of propolis in Turkey.*

components are aromatic and aliphatic acids and their esters and ketones, Erzurum propolis has a different structure and aromatic acid esters and alcohols are the basic components, and it is better than other samples. It was found to contain more amino acids. In the samples collected from Bursa region, it was determined that flavonones, terpenoids, flavones, aromatic acid esters, and ketones were the main amounts. In the samples from Bursa region, flavones, flavonones, and ketones were detected in very rich amounts. Silici and Kutluca [56] investigated the chemical profile and antimicrobial effect of propolis collected by three different honeybees in the same region and the same season in Erzurum (East Anatolia) with the GC–MS method and 48 compounds were identified 32 being new for propolis. They found high aromatic acid esters and amino acid contents and strong Gram-positive activity in *S. aureus*, weak Gram-negative efficiency in *E. coli* and *P. aeruginosa,* and yeast in *C. albicans*. Katırcıoglu and Mercan [57] studied the chemical components and antimicrobial activity of propolis samples obtained from different regions of Turkey. They collected *Antifungal Activity of Propolis against* Candida *Species: Propolis and Antifungal Action DOI: http://dx.doi.org/10.5772/intechopen.107172*

propolis samples from Trabzon, Erzurum, and Tekirdağ in 2004 and analyzed them by GC–MS chromatography method. They determined as major compounds flavonoids, crysin, apigenin, and flavonones in Trabzon propolis, crysin, flavonoids, apigenin, and flavonones in Erzurum propolis, and also crysin, apigenin, naringenin, flavonoids and flavonones in Tekirdağ propolis. These propolis specimens displayed a strong inhibitory effect against *Escherichia coli* and *Staphylococcus aureus* isolates, but they did not show inhibitory action on the *K. pneumoniae* and *Morganella morgagni* strains. Temiz et al. [58] researched the antimicrobial activities of 25 propolis specimens obtained from different geographical regions of Turkey on two food-borne pathogens, *Salmonella enteritidis* ATCC 13076 and *Listeria monocytogenes* ATCC 1462. The chemical compounds of ethyl alcohol extracts of propolis (EEP) specimens were identified by GC–MS. The main constituents were flavonoids, aromatic alcohols, aromatic acids and esters, terpenes, aliphatic carboxylic acids, and esters. Flavonoids were the only shared compound determined in all samples with different levels. Antimicrobial actions of the propolis samples were investigated at two different dilutions 10% and 1%. All propolis specimens at 10% dilution displayed high activity against both bacteria. Also, 1% dilution ratios were found high antimicrobial effect on *L. monocytogenes*.

#### **5.2 Antifungal properties of propolis and mechanisms of action**

The mechanisms of action of propolis are shown in **Figure 2**. The studies have reported that compounds such as flavonoids (especially pinocembrin) and phenolic compounds present in honey and propolis are responsible for their antifungal activity by affecting cytoplasmic membrane permeability and resulting in total leakage of cell components and inorganic ions, leading to complete cell death [46–48]. The ability of *C. albicans* to switch from yeast form to hyphae form plays an important role in its virulence. Recently, propolis has been used in the treatment of oral fungal diseases. Germ tube formation contributes to adherence in *C. albicans*. Propolis inhibits germ tube formation. The inhibition of *C. albicans* growth and germ tube formation by propolis is probably due to interaction with cellular sulphydryl compounds [49, 50]. Flavonoids, which are components of propolis, contain subgroups such as flavones, flavonols, flavanols (flavan-3-ol), isoflavones, anthocyanins, and chalcones [65]. The antifungal effect of flavonols such as kaempferol, quercetin, and myricetin has been defined to inhibit the growth and cell division of *C. albicans* [66]. Also, the flavanols subclass flavan-3-ol and gallotannin indicated an inhibitory effect on the growth and cell division of *C. albicans* [67]. Serpa et al. [68] found that flavones induced apoptosis in *C. albicans*. Terpenes showed an antibiofilm efficacy in the treatment of *Candida* infections related to device use in the hospital. Mechanism of action of terpenes; alteration of the cellular cytoplasmic membrane and induction of apoptosis [69]. Resistance to antifungal drugs used in the recent years has been considered as a health problem. Treatment difficulties are experienced especially in infections associated with biofilm formation in implanted medical devices such as cardiac, urinary, dental prosthesis, and catheters. *Candida* species are associated with biofilm-related infection. They are capable of colonizing medical implantable devices and mucosal membranes and develop resistance to commonly used conventional antifungal agents. *Candida* species may develop resistance to fluconazole and other azole groups during treatment or prophylaxis and high-level cross-resistance to azole groups often develops and also echinocandins [10, 70–72].

**Figure 2.** *The mechanisms of efficacy of propolis.*

#### **5.3 Studies on the antifungal properties of propolis**

Investigation on the antifungal efficacy of propolis is shown in **Table 3**. Hegazia et al. [33] found the highest antifungal activity of propolis on C. albicans, which was detected in Austrian propolis. Ota et al. [51] investigated the antifungal effect of Brazilian propolis against *Candida* species isolated from the saliva of patients with denture stomatitis. They reported that the antifungal activity of propolis was caused by phenolic constructions containing phenolic acids and their esters. In this *in vitro* study, the highest fungicidal activity showed C. albicans and others respectively were *C. tropicalis, C. krusei*, and *C. guilliermondii*. Also, in the *in vivo* study with propolis in these patients, a decrease in the number of *Candida* species was observed in the mouth rinse. Yarfani et al. [52] investigated the antifungal activity of Iranian propolis specimens to fluconazole-resistant C. albicans isolates obtained from HIV patients with oropharyngeal candidiasis. They found higher fungicidal activity in all fluconazole-resistant *C. albicans* specimens and they detected high amounts of phenolic acid and aromatic acids (especially caffeic acid) in each propolis specimen. These components of propolis have antifungal and antibacterial activities. Oliveira et al. [53] reported a high activity of propolis on *C. albicans, C. tropicalis, C. parapsilosis*, and other species obtained from patients with onychomycosis lesions. Fernandez-Calderon et al. [72] examined the activity of a new Spanish Ethanol Extract of Propolis (SEEP) on growth, cell surface hydrophobicity, adherence, and biofilm formation of *C. glabrata* to azole-resistant isolates obtained from different clinical specimens. The Spanish propolis had good antifungal activity within the range of 0.1– 0.4% (60–240 μg/mL), with a MIC50 and MIC90 of 0.2% (120 μg/mL). SEEP displayed perfect fungicidal effect on *C. glabrata* strains, with an MFC50 of 0.4% (240 μg/mL), an MFC90 of 0.8% (480 μg/mL) and range 0.4−>1.5%. SEEP did not exhibit a clear activity on surface hydrophobicity and adhesion, but an inhibitory activity on biofilm formation was displayed at sub-inhibitory concentrations (0.1 and 0.05%) with a significant decrease in biofilm formation. Capoci et al. [73] observed the antifungal effect of propolis and inhibition of biofilm production in strains of *C. albicans* isolated from patients with vulvovaginal candidiasis (VVC). The MIC of propolis extract ranged from 68.35 to 546.87 μg/mL of total phenol ingredient in gallic acid. Propolis

*Antifungal Activity of Propolis against* Candida *Species: Propolis and Antifungal Action DOI: http://dx.doi.org/10.5772/intechopen.107172*


**Table 3.**

*Mechanisms of action and antifungal activity of propolis.*

solution inhibited biofilm formation by *C. albicans* in patients with VVC. Freires et al. [74] analyzed the chemical properties and antifungal effect of Brazilian propolis (type 3 and type 13) on *Candida* species (*C. albicans, C. dubliniensis, C. glabrata, C. tropicalis, C. parapsilosis, and C. krusei*). Propolis ethanol extracts were examined by GC–MS. In the EEP 3 were found the phenolic compounds *p-*coumaric acid, caffeic acid phenetyl ester, kaempferol, and quercetin. In the EEP 13 were identified isoflavonoids such as vestitol and formononetin. All extracts inhibited biofilm formation. Brazilian propolis has frequently fungistatic effect. Ladnut et al. [75] examined the antifungal and antivirulence effects of biologically synthesized Ethanolic Extract of Propolis-Loaded poly (lactic-co-glycolic acid) PLGA Nanoparticles (EEP-NPs) on *C. albicans.* EEP-NPs showed a higher antifungal effect than EEP in free form and reduced the effect of virulence factors such as adhesion, hyphal germination, biofilm formation, and invasion.

In conclusion, resistance to antifungals used in traditional treatment such as azole groups and also echinocandins in *Candida* species has increased due to the adhesion capacity, germ tube, and biofilm formation of *Candida*. Propolis is a resinous natural, non-toxic product collected by honeybees. There are many in vitro studies on the antimicrobial and antifungal properties of propolis in the world. However, clinical studies examining its effects on animals and humans are very limited. For the safe use of propolis, further and more clinical studies should be performed to develop alternative therapies with natural products like propolis that complement conventional treatments.

Candida *and Candidiasis*

#### **Author details**

Emine Kucukates Istanbul University-Cerrahpasa, Cardiology Institute, Istanbul, Turkey

\*Address all correspondence to: eates2002@yahoo.com

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Antifungal Activity of Propolis against* Candida *Species: Propolis and Antifungal Action DOI: http://dx.doi.org/10.5772/intechopen.107172*

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### *Edited by Tulin Askun*

This book collates up-to-date information about *Candida* and candidiasis, covering the following topics: diversity and genetic structure of the genus *Candida*, invasion biology of candidiasis, pathogenicity, drug resistance, antifungal susceptibility, antifungal-resistant *Candida* strains, antifungal-resistant genes among resistant isolates, molecular mechanisms of antifungal resistance, diagnosis and targeted therapy of candidiasis, cytotoxicity, biofilms, *Candida albicans* and non-*C. albicans,*  Covid-19 patients and proteomics, pustules, systemic therapies, topical therapies, new effective compounds against *Candida* spp. cutaneous candidiasis, oropharyngeal candidiasis, oesophageal candidiasis, vulvovaginal candidiasis, intestinal candidiasis, invasive candidiasis, molecular methods in the diagnosis of *Candida* strains, hostpathogen interactions, interactions between *Candida* and cancer, antifungal drug discovery, natural compounds effective against *Candida* strains, and novel active compounds for candidiasis treatment.

Published in London, UK © 2023 IntechOpen © CIPhotos / iStock

*Candida*

and Candidiasis

*Candida* and Candidiasis

*Edited by Tulin Askun*