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. 2021 May 5;7(5):360. doi: 10.3390/jof7050360

Plant Preparations and Compounds with Activities against Biofilms Formed by Candida spp.

Tomasz M Karpiński 1,*, Marcin Ożarowski 2, Agnieszka Seremak-Mrozikiewicz 3,4,5, Hubert Wolski 3,6, Artur Adamczak 7
Editors: Célia F Rodrigues, Jesus A Romo
PMCID: PMC8147947  PMID: 34063007

Abstract

Fungi from the genus Candida are very important human and animal pathogens. Many strains can produce biofilms, which inhibit the activity of antifungal drugs and increase the tolerance or resistance to them as well. Clinically, this process leads to persistent infections and increased mortality. Today, many Candida species are resistant to drugs, including C. auris, which is a multiresistant pathogen. Natural compounds may potentially be used to combat multiresistant and biofilm-forming strains. The aim of this review was to present plant-derived preparations and compounds that inhibit Candida biofilm formation by at least 50%. A total of 29 essential oils and 16 plant extracts demonstrate activity against Candida biofilms, with the following families predominating: Lamiaceae, Myrtaceae, Asteraceae, Fabaceae, and Apiacae. Lavandula dentata (0.045–0.07 mg/L), Satureja macrosiphon (0.06–8 mg/L), and Ziziphora tenuior (2.5 mg/L) have the best antifungal activity. High efficacy has also been observed with Artemisia judaica, Lawsonia inermis, and Thymus vulgaris. Moreover, 69 plant compounds demonstrate activity against Candida biofilms. Activity in concentrations below 16 mg/L was observed with phenolic compounds (thymol, pterostilbene, and eugenol), sesquiterpene derivatives (warburganal, polygodial, and ivalin), chalconoid (lichochalcone A), steroidal saponin (dioscin), flavonoid (baicalein), alkaloids (waltheriones), macrocyclic bisbibenzyl (riccardin D), and cannabinoid (cannabidiol). The above compounds act on biofilm formation and/or mature biofilms. In summary, plant preparations and compounds exhibit anti-biofilm activity against Candida. Given this, they may be a promising alternative to antifungal drugs.

Keywords: Candida, biofilm, treatment, antifungals, natural compounds, essential oil, extract, minimal inhibitory concentration (MIC)

1. Introduction

The genus Candida contains about 150 species; however, most are environmental organisms. The most medically important is Candida albicans, which accounts for about 80% of infections. C. albicans causes more than 400,000 cases of bloodstream life-threatening infections annually, with a mortality rate of about 42% [1]. Candida non-albicans species that are mainly responsible for infections are C. glabrata, C. parapsilosis, C. tropicalis, C. krusei, and C. dubliniensis [2]. Less frequently identified are C. guilliermondii, C. lusitaniae, C. rugosa, C. orthopsilosis, C. metapsilosis, C. famata, C. inconspicua, and C. kefyr [3].

C. albicans is a member of the commensal microflora. It colonizes the oral mucosal surface of 30–50% of healthy people. The rate of carriage increases with age and in persons with dental prostheses up to 60% [4,5,6]. Opportunistic infection caused by Candida species is termed candidiasis. At least one episode of vulvovaginal candidiasis (or thrush) concerns 50 to 75% of women of childbearing age [7]. Candidiasis can also affect the oral cavity, penis, skin, nails, cornea, and other parts of the body. In immunocompromised persons, untreated candidiasis poses the risk of systemic infection and fungemia [5,8]. Candida can be an important etiological factor in the infection of chronic wounds that are difficult to treat; this is mainly related to the production of biofilm [9].

Treatment of candidiasis depends on the infection site and the patient’s condition. According to guidelines, vulvovaginal candidiasis should be treated with oral or topical fluconazole; however, regarding C. glabrata infection, topical boric acid, nystatin, or flucytosine is suggested. In oropharyngeal candidiasis, the treatment options include clotrimazole, miconazole, or nystatin, and in severe disease, fluconazole or voriconazole. In candidemia and invasive candidiasis, the drugs of choice are echinocandins (caspofungin, micafungin, anidulafungin), fluconazole, or voriconazole; in resistant strains, amphoteticin B is used. In selected cases of candidemia caused by C. krusei, voriconazole is recommended [10,11,12]. More details can be found in the Guidelines of the Infectious Diseases Society of America [12] and the European Society of Clinical Microbiology and Infectious Diseases [11]. Increasingly, Candida species are becoming resistant to drugs. Marak and Dhanashree [13] tested the resistance of 90 Candida strains isolated from different clinical samples, such as pus, urine, blood, and body fluid. Their study revealed that about 41% of C. albicans strains are resistant to fluconazole and voriconazole. Simultaneously, about 41% of C. tropicalis strains are resistant to voriconazole and about 36% of strains to fluconazole. In strains of C. krusei, about 23% are resistant to fluconazole and about 18% to voriconazole. Rudramurthy et al. [14] studied resistance in C. auris, which is considered a multiresistant pathogen. Among 74 strains obtained from patients with candidemia, over 90% of strains were resistant to fluconazole and about 73% to voriconazole. Virulence factors of Candida species include the secretion of hydrolases, the transition of yeast to hyphae, phenotypic switching, and biofilm formation [15,16]. All microorganisms in biofilm form are more resistant to antimicrobial and host factors, which leads to difficulties in eradication [17]. It has also been shown that resistance to drugs increases significantly in the case of Candida biofilm occurrence. Biofilm prevents the spread of antifungals; moreover, fluconazole is bound by the biofilm matrix [18]. The formation of a Candida biofilm during infection increases mortality, length of hospital stay, and cost of antifungal therapy [19].

Due to the above, new antifungal drugs are sought that could effectively combat not only planktonic fungi but also fungal biofilms. The natural compounds offer promise, with many acting on Candida species or biofilms in vitro [20].

The aim of this review was to present plant-derived natural compounds that have an effect against biofilms formed by Candida species.

2. Materials and Methods

In this review, publications available in PubMed and Scopus databases and through the Google search engine were taken into account. The following keywords and their combinations were used: “antifungal,” “Candida,” “anti-biofilm,” “biofilm,” “plant,” “compound,” “extract,” and “essential oil.” The principal inclusion criterion was the inhibition of biofilm formation by at least 50%. We focused on biofilm inhibition assays, in which the time of culture allowed for Candida biofilm maturation was at least 24 hours. Articles from the year 2000 to the present were taken into account. All articles published in predatory journals were rejected.

3. Results and Discussion

3.1. Plant Preparations That Display Activity against Candida Biofilms

The present review includes 60 articles in which Candida biofilm formation was inhibited by at least 50%. It has been shown that preparations from 34 plants demonstrate activity against Candida biofilms. Among them were 29 essential oils and 16 extracts. The plants from the following families dominated: Lamiaceae (6 species in 5 genera), Myrtaceae (5 species in 4 genera), Asteraceae (4 species in 4 genera), Fabaceae (4 species in 3 genera), and Apiacae (4 species in 2 genera).

Plants from the Lamiaceae family had the best antifungal activity, including Lavandula dentata (0.045–0.07 mg/L) [21], Satureja macrosiphon (0.06–8 mg/L) [22], and Ziziphora tenuior (2.5 mg/L) [23]. Artemisia judaica (2.5 mg/L) from the Asteraceae family [24], Lawsonia inermis (2.5–12.5 mg/L) from the Lythraceae family [25], and Thymus vulgaris (12.5 mg/L) from the Lamiaceae family [26] likewise exhibited good antifungal activity (Table 1). All preparations were essential oils, with the exception of Lawsonia inermis, which was an extract. Most of the plant preparations presented in Table 1 acted on biofilm formation and/or mature biofilms.

Table 1.

Antifungal (MICs) and anti-biofilm (inhibition >50%) activity of plant preparations (essential oils or extracts).

Name of Plant
(Family)		 Main Compounds Presented in the Reference
(EO: Essential Oil)		 Targeted Species of Candida MICs
(mg/L; mL/L)		 Inhibition of Biofilm Formation by at Least 50% (mg/L; mL/L) Inhibited Stage of Biofilm; Method of Biofilm Detection Ref.
Acorus calamus var. angustatus Besser = A. tatarinowii Schott
(Acoraceae)		 EO: asaraldehyde, 1-(2,4,5-trimethoxyphenyl)-1,2-propanediol, α-asarone, β-asarone, γ-asarone,
acotatarone C		 C. albicans 51.2 50–200 Mature biofilm; crystal violet and fluorescence microscopy [27]
Allium sativum L.
(Amaryllidaceae)		 Extract: allicin C. albicans 400 60 Biofilm formation; XTT [28]
Aloysia gratissima (Aff & Hook).Tr
(Verbenaceae)		 EO: E-pinocamphone (16.07%), β-pinene (12.01%), guaiol (8.53%), E-pinocarveol acetate (8.19%) C. albicans 15 500 Biofilm formation; crystal violet [29]
Artemisia judaica L.
(Asteraceae)		 EO: piperitone (30.4%), camphor (16.1%), ethyl cinnamate (11.0%), chrysanthenone (6.7%) C. albicans 1.25 2.5 Mature biofilm; XTT [24]
C. guillermondii 1.25 2.5
C. krusei 1.25 2.5
C. parapsilosis 1.25 2.5
C. tropicalis 1.25 2.5
Buchenavia tomentosa Eichler
(Combretaceae)		 Extract: gallic acid, kaempferol, epicatechin, ellagic acid, vitexin, and corilagin C. albicans 625 312.5 Biofilm formation and mature biofilm; culture [30]
Chamaecostus cuspidatus (Nees & Mart.) C.Specht & D.W.Stev.
(Costaceae)		 Extract: dioscin,
aferoside A, aferoside C		 C. albicans 250 15.62 Biofilm formation and mature biofilm; MTT [31]
Cinnamomum verum J. Presl
(Lauraceae)		 EO: eugenol (77.22%), benzyl benzoate (4.53%), trans-caryophyllene (3.39%), acetyl eugenol (2.75%), linalool 2.11% C. albicans 1000 150 Biofilm adhesion; XTT [32]
C. dubliniensis 1000 200
C. tropicalis 1000 350
Citrus limon (L.) Osbeck
(Rutaceae)		 EO: limonene (53.4%), neral (11%), geraniol (9%), trans-limonene oxide (7%), nerol (6%) C. albicans 500 2000 Biofilm formation and mature biofilm; XTT [33]
C. glabrata 250 1000
C. krusei 500 125
C. orthopsilosis 500 1000
C. parapsilosis 500 2000
C. tropicalis 250 2000
Copaifera paupera (Herzog) Dwyer
(Fabaceae)		 Extract: galloylquinic acids, quercetrin, afzelin C. glabrata 5.89 46.87 Biofilm formation and mature biofilm; XTT [34]
Copaifera reticulata Ducke
(Fabaceae)		 Extract: galloylquinic acids, quercetrin, afzelin C. glabrata 5.89 46.87 Biofilm formation and mature biofilm; XTT [34]
Coriandrum sativum L.
(Apiaceae)		 EO: 1-decanol (33.91%), E-2-decen-1-ol (23.59%), 2-dodecen-1-ol (13.06%), E-2-tetradecen-1-ol (5.46%) C. albicans 7 250 Biofilm formation; crystal violet [29]
EO: decanal (19.09%), trans-2-decenal (17.54%), 2-decen-1-ol (12.33%), cyclodecane (12.15%) C. albicans 15.6 62.5–125 Biofilm adhesion; crystal violet [35]
C. dubliniensis 31.2 62.5–125
C. rugosa 15.6 62.5
C. tropicalis 31.2 31.25–250
Croton eluteria (L.) W.Wright
(Euphorbiaceae)		 EO: α-pinene (29.37%), β-pinene (19.35%), camphene (10.31%), 1,8-cineole (9.68%) C. albicans 4000 5–500 Biofilm formation; confocal laser microscopy [36]
Cupressus sempervirens L.
(Cupressaceae)		 EO: sabinene (20.3%), citral (20%), terpinene-4-ol (15.4%), α-pinene (8%) C. albicans 250 1000 Biofilm formation and mature biofilm; XTT [33]
C. glabrata 31.25 250
C. krusei 62.5 62.5
C. orthopsilosis 31.25 125
C. parapsilosis 62.5 500
C. tropicalis 250 500
Cymbopogon citratus (DC.) Stapf
(Poaceae)		 EO: no composition C. albicans 180–360 22.5–180 Biofilm formation; XTT [37]
Cymbopogon martini (Roxb.) W.Watson
(Poaceae)		 EO: no composition C. albicans 16,800 800 Biofilm formation; XTT [38]
Cymbopogon nardus (L.) Rendle
(Poaceae)		 EO: citronellal (27.87%),
geraniol (22.77%), geranial (14.54%), citronellol (11.85%), neral (11.21%)		 C. albicans 1000 2500–5000 Biofilm adhesion; XTT [39]
C. krusei 250–500 2500
C. parapsilosis 500–1000 5000–10,000
Cyperus articulatus L.
(Cyperaceae)		 EO: α-pinene (5.72%), mustakone (5.66%), α-bulnesene (5.02%), α-copaene (4.97%) C. albicans 125 250 Biofilm formation; crystal violet [29]
Eucalyptus sp.
(Myrtaceae)		 EO: no composition C. albicans 8 8 Mature biofilm; luminescence [40]
Eucalyptus globulus Labill.
(Myrtaceae)		 EO: 1,8-cineole (75.8%), p-cymene (7.5%), α-pinene (7.4%), limonene (6.4%) C. albicans 219 11,250–22,500 Mature biofilm; atomic force microscopy [41]
C. glabrata 219 11,250–22,500
C. tropicalis 885 11,250–22,500
EO: no composition C. albicans 8400 500 Biofilm formation; XTT [38]
Eugenia brasiliensis Lam. (Myrtaceae) Extract: no composition C. albicans 15.62–31.25 156 Mature biofilm; scanning electron microscopy [42]
Eugenia leitonii Legrand nom. inval.
(Myrtaceae)		 Extract: no composition C. albicans 15.62–250 156 Mature biofilm; scanning electron microscopy [42]
Helichrysum italicum (Roth) G.Don
(Asteraceae)		 EO: α-pinene (27.64%), γ-elemene (23.84%), β-caryophyllene (13.05%), α-longipinene (11.25%) C. albicans 6000 10–500 Biofilm formation; confocal laser microscopy [36]
Laserpitium latifolium L.
(Apiaceae)		 Extract: laserpitine C. albicans 1250 6300 Mature biofilm; luminescence [43]
C. krusei 1250 6300
Laserpitium ochridanum Micevski
(Apiaceae)		 Extract: isomontanolide,
montanolide, tarolide		 C. albicans 5000 10,000 Mature biofilm; luminescence [43]
C. krusei 5000 10,000
Laserpitium zernyi Hayek = L. siler subsp. zernyi (Hayek) Tutin
(Apiaceae)		 Extract: isomontanolide,
montanolide, tarolide		 C. albicans 7500 15,000 Mature biofilm; luminescence [43]
C. krusei 7500 37,500
Lavandula dentata L.
(Lamiaceae)		 EO: eucalyptol (42.66%), β-pinene (8.59%), trans-α-bisabolene (6.34%), pinocarveol (6.3%) C. albicans 0.15–0.18 0.045–0.07 Mature biofilm; XTT [21]
Lawsonia inermis L.
(Lythraceae)		 Extract: no composition C. albicans 10 2.5–12.5 Mature biofilm; MTT [25]
Lippia sidoides Cham.
(Verbenaceae)		 EO: thymol (65.76%), p-cymene (17.28%), α-caryophyllene (10.46%), cyclohexanone (6.5%) C. albicans 250 500 Biofilm formation; crystal violet [29]
Litsea cubeba (Lour.) Pers.
(Lauraceae)		 EO: limonene (37%), neral (31.4%), citral (12%), linalool (4%) C. albicans 500 2000 Biofilm formation and mature biofilm; XTT [33]
C. glabrata 250 2000
C. krusei 62.5 250
C. orthopsilosis 250 2000
C. parapsilosis 500 1000
C. tropicalis 1000 2000
Mentha × piperita L.
(Lamiaceae)		 EO: menthol (32.93%), menthone (24.41%), 1,8-cineole (7.89%) C. albicans 1–10 10 Biofilm formation; MTT [44]
EO: no composition C. albicans 11,600 800 Biofilm formation; XTT [38]
Mikania glomerata Spreng
(Asteraceae)		 EO: germacrene D (38.29%), α-caryophyllene (9.49%), bicyclogermacrene (7.98%), caryophyllene oxide (4.28%) C. albicans 250 500 Biofilm formation; crystal violet [29]
Myrtus communis L.
(Myrtaceae)		 EO: α-pinene (39.8%), 1,8-cineole (24.8%), limonene (10.7%), linalool (6.4%) C. albicans 1250–10,000 None or 1250 No data; no data [45]
C. parapsilosis 1250 to >16,000 1250
C. tropicalis 1250–16,000 1250
Ononis spinosa L.
(Fabaceae)		 Extract: kaempherol-O-dihexoside, kaempherol-O-hexoside-pentoside, kaempherol-O-hexoside, quercetin-O-hexoside-pentoside, acetylquercetin-O-hexoside C. albicans 620 10,000 Mature biofilm; luminescence [46]
C. krusei 620 5000
C. tropicalis 310 10,000
Pelargonium graveolens L’Hér.
(Geraniaceae)		 EO: geraniol (42.3%), linalool (20.1%), citronellol (11.1%), menthone (8.0%) C. albicans 125 4000–8000 Mature biofilm; XTT [47]
Piper claussenianum (Miq.) C. DC.
(Piperaceae)		 EO: nerolidols C. albicans 4100–9600 2400–12,600 Mature biofilm; MTT [48]
Portulaca oleracea L.
(Portulacaceae)		 Extract: no composition C. albicans 10 12.5 Mature biofilm; MTT [25]
Punica granatum L.
(Lythraceae)		 Extract: ellagic acid C. albicans 1000 100–750 Biofilm formation and mature biofilm; crystal violet [49]
Santolina impressa Hoffmanns. & Link
(Asteraceae)		 EO: β-pinene (22.5%), 1,8-cineole (10.0%), limonene (9.1%), camphor (8.1%), β-phellandrene (8.0%) C. albicans 540 70–1050 Biofilm formation; XTT [50]
Satureja hortensis L.
(Lamiaceae)		 EO: thymol (45.9%),
gamma-terpinen (16.71%), carvacrol (12.81%), p-cymene (9.61%)		 C. albicans 200–400 400–4800 Biofilm adhesion, formation, and mature biofilm; MTT [51]
Satureja macrosiphon (Coss.) = Micromeria macrosiphon Coss.
(Lamiaceae)		 EO: linalool (28.46%), borneol (16.22%), terpinene-4-ol (14.58%), cis-sabinene hydrate (12.96%) C. albicans 0.06–4 0.06–8 Biofilm formation; XTT [22]
C. dubliniensis 0.25–4 2–8
Syzygium aromaticum (L.) Merr. & L.M.Perry = Eugenia caryophyllus (Spreng.) Bullock & S.G.Harrison
(Myrtaceae)		 EO: no composition C. albicans 100–200 50 Biofilm formation; XTT [37]
EO: no composition C. albicans 48,000 3300 Biofilm formation; XTT [38]
Thymus vulgaris L.
(Lamiaceae)		 EO: thymol (54.73%), carvacrol (12.42%), terpineol (4.00%), nerol acetate (2.86%), fenchol (0.5%) C. albicans 1.56–25 12.5 Biofilm formation; absorbance, crystal violet, and scanning electron microscopy [26]
C. tropicalis 25–50 12.5
Warburgia ugandensis Sprague
(Canellaceae)		 Extract: ugandenial A, warburganal, polygodial, alpha-linolenic acid ALA C. albicans Lack of data 1000 Biofilm formation and mature biofilm; XTT and confocal laser microscopy [52]
C. glabrata Lack of data 1000
Ziziphora tenuior L.
(Lamiaceae)		 EO: pulegone (46.8%),
p-menth-3-en-8-ol (12.5%),
isomenthone (6.6%),
8-hydroxymenthone (6.2%),
isomenthol (4.7%)		 C. albicans 1.25 2.5 Mature biofilm; XTT [23]
Zuccagnia punctata L.
(Fabaceae)		 Extract: no composition C. albicans 400 100 Biofilm formation and mature biofilm; XTT and crystal violet [53]
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Legend: MIC—minimal inhibitory concentration; XTT—reduction assay of 2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-5-[carbonyl(phenylamino)]-2H-tetrazolium hydroxide; MTT—reduction assay of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide [54,55].

Antibiofilm activity may vary between plants in the same family. For example, in the Lamiaceae family, essential oil from Lavandula dentata acted against C. albicans biofilm at concentrations of 0.045–0.07 µL/mL [21], while essential oil from Satureja hortensis acted against the same biofilm at concentrations of 400–4800 mg/L [51]. There may also be large differences within the same species, due to various reasons. This may be influenced by, for example, different research methodologies, the use of different strains of fungi, and different chemical compositions depending on the plant variety, country, and season of harvest. A notable example of such a difference is observed with Mentha × piperita. In studies by Benzaid et al. [44], essential oil of M. piperita acted against Candida biofilm at a concentration of 10 µL/mL. However, the work of Agarwal et al. [38] showed that the same essential oil was active at 800 µL/mL.

Changes in the content of active substances were described by Gonçalves et al. [56]. They showed that in essential oil from Mentha cervina collected in August, the amount of isomenthone was 8.7% and pulegone was 75.1%. However, in essential oil collected in February, the ratio of the two compounds reversed and amounted to 77.0% for isomenthone and 12.9% for pulegone. The method of obtaining the compounds likewise had an influence on their content in the final essential oil. In a study by Ćavar et al. [57], the composition of essential oils of Calamintha glandulosa differed depending on the extraction method. The level of menthone was 3.3% using aqueous reflux extraction, 4.7% using hydrodistillation, and 8.3% using steam distillation, while the concentration of shisofuran was only 0.1% using hydrodistillation and steam distillation, while aqueous reflux yielded 9.7%.

3.2. Plant Compounds That Display Activity against Candida Biofilm

It has been shown that 69 compounds obtained from plants demonstrate activity against Candida biofilms (Table 2). Among these, the most common are monotherpenes (20), followed by sesquiterpene lactones (7) and sesquiterpenes (6). Another big group is also phenolic compounds, including phenols (6), phenolic acids (5), phenolic aldehydes (2), polyphenols (2), and phenolic alcohol (1).

Table 2.

Antifungal and antibiofilm activity of plant compounds.

Active Compound Example of Plant Origin Targeted Fungus MICs
(mg/L, mL/L)		 Inhibition of Biofilm Formation by at Least 50% (mg/L, mL/L) Inhibited Stage of Biofilm; Method of Biofilm Detection Ref.
Antidesmone
(alkaloid)		 Waltheria indica,
W. brachypetala 		C. albicans 32 16 Mature biofilm; XTT [63]
C. glabrata >32 16
C. krusei 16 16
C. parapsilosis 4 16
C. tropicalis >32 16
Anisaldehyde
(phenolic aldehyde)		 Pimpinella anisum ,
Foeniculum vulgare 		C. albicans 500 500 Mature biofilm; XTT, crystal violet, and inverted light microscopy [68]
Anisic acid
(phenolic acid)		 Pimpinella anisum C. albicans 4000 4000 Mature biofilm; XTT, crystal violet, and inverted light microscopy [68]
Anisyl alcohol
(phenolic alcohol)		 Pimpinella anisum C. albicans 31 500 Mature biofilm; XTT, crystal violet, and inverted light microscopy [68]
Baicalein
(flavonoid)		 Scutellaria baicalensis,
S. lateriflora 		C. albicans No data 4–32 Biofilm formation; XTT [62]
Camphene
(monotherpene)		 Croton eluteria,
Cinnamomum verum 		C. albicans No data 500 Biofilm formation; confocal laser microscopy [36]
C. albicans 1000 2000 Mature biofilm; XTT, crystal violet, and inverted light microscopy [69]
Camphor
(bicyclic monotherpene)		 Cinnamomum camphora,
Artemisia annua 		C. albicans 125–250 Not or 62.5–250 Biofilm formation; crystal violet and absorbance [70]
C. glabrata 175 Not
C. krusei 350 Not
C. parapsilosis 125 Not
C. tropicalis 175 175
Cannabidiol
(cannabinoid)		 Cannabis sativa C. albicans No data 12.5–100 Biofilm formation; confocal microscopy [66]
Carvacrol
(phenol)		 Thymus serpyllum,
Carum carvi,
Origanum vulgare 		C. albicans 250 500 Mature biofilm; XTT, crystal violet, and inverted light microscopy [69]
100–20,000 300–1250 Mature biofilm; XTT [71]
1000 750–1500 Biofilm formation; MTT [72]
C. glabrata 100–20,000 300–1250 Mature biofilm; XTT [71]
C. parapsilosis 100–20,000 300–1250
Carvene/Limonene
(monotherpene)		 Citrus × aurantium,
Citrus limon 		C. albicans 1000 4000 Mature biofilm; XTT, crystal violet, and inverted light microscopy [69]
Carvone/Carvol
(monotherpene)		 Carum carvi,
Mentha spicata 		C. albicans >4000 250 Mature biofilm; XTT, crystal violet, and inverted light microscopy [69]
β-Caryophyllene
(sesquiterpene)		 Helichrysum italicum,
Caryophyllusaromaticus 		C. albicans No data 100–500 Biofilm formation; confocal laser microscopy [36]
1,4-Cineole
(monotherpene)		 Rosmarinus officinalis ,
Thymus vulgaris 		C. albicans >4000 4000 Mature biofilm; XTT, crystal violet, and inverted light microscopy [69]
1,8-Cineole/Eucalyptol
(monotherpene)		 Eucalyptus globulus,
Salvia officinalis,
Pinus sylvestris 		C. albicans 4000 4000 Mature biofilm; XTT, crystal violet, and inverted light microscopy [69]
8 4 Mature biofilm; luminescence [40]
3000–23,000 Not or 3000–23,000 Biofilm formation; crystal violet and absorbance [70]
C. glabrata 2000 Not
C. krusei 4000 2000–4000
C. parapsilosis 2000 1000–2000
C. tropicalis 4000 2000–4000
Cinnamaldehyde
(aldehyde)		 Cinnamomum sp.,
Apium graveolens 		C. albicans 62 125 Mature biofilm; XTT, crystal violet, and inverted light microscopy [68]
50–400 25–200 Mature biofilm; XTT [58]
Cinnamic acid
(phenolic acid)		 Cinnamomum sp. C. albicans 2000 4000 Mature biofilm; XTT, crystal violet, and inverted light microscopy [68]
Citral
(monotherpene)		 Melissa officinalis,
Backhousia citriodora 		C. albicans 500 1000 Mature biofilm; XTT, crystal violet, and inverted light microscopy [69]
Citronellal
(monotherpene)		 Cymbopogon citratus ,
Melissa officinalis 		C. albicans 500 1000 Mature biofilm; XTT, crystal violet, and inverted light microscopy [69]
β-Citronellol
(monotherpene)		 Melissa officinalis,
Pelargonium roseum 		C. albicans 500 1000 Mature biofilm; XTT, crystal violet, and inverted light microscopy [69]
Cuminaldehyde
(monotherpene)		 Carum carvi ,
Cinnamomum verum 		C. albicans 1000 to >4000 6000–7000 Biofilm formation; MTT [72]
p-Cymene
(monotherpene)		 Thymus vulgaris,
Eucalyptus sp.		 C. albicans 2000 4000 Mature biofilm; XTT, crystal violet, and inverted light microscopy [69]
8-Deoxoantidesmone
(alkaloid)		 Waltheria indica C. albicans 16 32 Mature biofilm; XTT [63]
C. glabrata >32 32
C. krusei 32 32
C. parapsilosis 32 32
C. tropicalis >32 32
2′,4′-Dihydroxy-3′-methoxychalcone
(chalcone)		 Zuccagnia punctata,
Oxytropis falcata 		C. albicans 100 25 Biofilm formation and mature biofilm; XTT and crystal violet [53]
Dioscin
(steroidal saponin)		 Dioscorea sp.,
Chamaecostus 		C. albicans 3.9–15.62 3.9–31.25 Biofilm formation and mature biofilm; MTT [31]
Ellagic acid
(polyphenol)		 Punica granatum L. C. albicans 75–100 25–40 Biofilm formation and mature biofilm; crystal violet [49]
Emodin
(anthraquinone)		 Rheum palmatum,
Frangula alnus 		C. albicans 12.5–50 Not or 100–400 Biofilm adhesion; MTT [73]
4α,5α-Epoxy-10α,14H-1-epi-inuviscolide
(sesquiterpene lactone)		 Carpesium macrocephalum C. albicans >128 38 Biofilm formation and mature biofilm; XTT [67]
Eugenol
(phenol)		 Syzygium aromaticum ,
Cinnamomum sp. 		C. albicans 50–400 12.5–200 Mature biofilm; XTT [58]
250 500 Mature biofilm; XTT, crystal violet, and inverted light microscopy [69]
500 500 Mature biofilm; XTT, crystal violet, and inverted light microscopy [68]
1200 10,000–80,000 Mature biofilm; XTT [59]
Farnesol
(sesquiterpene)		 Tilia sp.,
Cymbopogon sp.		 C. albicans 1000 500 Mature biofilm; XTT, crystal violet, and inverted light microscopy [68]
1000 500 Mature biofilm; XTT, crystal violet, and inverted light microscopy [69]
Gallic acid
(phenolic acid)		 Polygonum sp.,
Buchenavia tomentosa 		C. albicans 5000 2500 Biofilm formation and mature biofilm; culture [30]
Geraniol
(monotherpene)		 Pelargonium graveolens,
Rosa sp.		 C. albicans 1000 1000 Mature biofilm; XTT, crystal violet, and inverted light microscopy [69]
C. albicans 100–20,000 300–1250 Mature biofilm; XTT [71]
C. albicans No data 1000–8000 Mature biofilm; XTT [47]
C. glabrata 100–20,000 300–1250 Mature biofilm; XTT [71]
C. parapsilosis 100–20,000 300–1250
Guaiacol
(phenol)		 Guaiacum officinale ,
Apium graveolens 		C. albicans 500 1000 Mature biofilm; XTT, crystal violet, and inverted light microscopy [68]
Hydroxychavicol
(phenol)		 Piper betle C. albicans 125–500 125–1000 Biofilm formation and mature biofilm; XTT [74]
β-Ionone
(carotenoid)		 Lawsonia inermis ,
Camellia sinensis 		C. albicans 250 250 Mature biofilm; XTT, crystal violet, and inverted light microscopy [69]
Isomontanolide
(sesquiterpenic lactone)		 Laserpitium ochridanum,
L. zernyi 		C. albicans 50 250 Mature biofilm; luminescence [43]
C. krusei 200 250
Isopulegol
(monotherpene)		 Mentha rotundifolia,
Melissa officinalis 		C. albicans >4000 250 Mature biofilm; XTT, crystal violet, and inverted light microscopy [69]
Ivalin
(sesquiterpene lactone)		 Geigeria aspera,
Carpesium macrocephalum 		C. albicans >128 15.4 Biofilm formation and mature biofilm; XTT [67]
Laserpitine
(sesquiterpene lactone)		 Laserpitium latifolium,
Laserpitiumhalleri 		C. albicans 200 400 Mature biofilm; luminescence [43]
C. krusei 200 400
Lichochalcone A
(chalconoid)		 Glycyrrhiza sp. C. albicans 6.25–12.5 0.2–20 Biofilm formation; crystal violet [61]
Linalool
(monotherpene)		 Lavandula officinalis,
Pelargonium graveolens 		C. albicans No data 100–500 Biofilm formation; confocal laser microscopy [36]
2000 1000 Mature biofilm; XTT, crystal violet, and inverted light microscopy [69]
No data 1000–8000 Mature biofilm; XTT [47]
α-Longipinene
(sesquiterpene)		 Croton eluteria,
Helichrysum italicum 		C. albicans No data 100–500 Biofilm formation; confocal laser microscopy [36]
Menthol
(monotherpene)		 Mentha spp. C. albicans >4000 2000 Mature biofilm; XTT, crystal violet, and inverted light microscopy [69]
2500 10,000–80,000 Mature biofilm; XTT [59]
Montanolide
(sesquiterpene lactone)		 Laserpitium ochridanum,
L. zernyi 		C. albicans 200 400 Mature biofilm; luminescence [43]
C. krusei 200 400
Morin
(flavonoid)		 Prunus dulcis ,
Morus alba 		C. albicans 150 37.5–600 Biofilm formation; crystal violet [75]
Myrcene
(monotherpene)		 Humulus lupulus,
Cannabis sativa 		C. albicans 1000 2000 Mature biofilm; XTT, crystal violet, and inverted light microscopy [69]
Nerol
(monotherpene)		 Citrus × aurantium,
Humulus lupulus 		C. albicans 2000 500 Mature biofilm; XTT, crystal violet, and inverted light microscopy [69]
Nerolidols
(sesquiterpene)		 Citrus × aurantium,
Piper claussenianum 		C. albicans 18,600–62,500 2500–10,000 Mature biofilm; MTT [48]
α-Pinene
(monotherpene)		 Pinus sylvestris,
Picea abies 		C. albicans 3125 3125 Biofilm formation; XTT [76]
β-Pinene
(monotherpene)		 Pinus sylvestris,
Picea abies 		C. albicans 2000 4000 Mature biofilm; XTT, crystal violet, and inverted light microscopy [69]
187 187 Biofilm formation; XTT [76]
Polygodial
(sesquiterpene)		 Warburgia ugandensis, Polygonum hydropiper C. albicans 4.1 10.8 Biofilm formation and mature biofilm; XTT and confocal laser microscopy [52]
C. glabrata 94.1 50.6–61.9
Pterostilbene
(polyphenol)		 Pterocarpus marsupium, Pterocarpus santalinus,
Vitis vinifera 		C. albicans No data 8–32 Biofilm formation and mature biofilm; XTT [65]
Riccardin D
(macrocyclic bisbibenzyl)		 Dumortiera hirsuta C. albicans 16 8–64 Mature biofilm; XTT [64]
Salicylaldehyde
(phenolic aldehyde)		 Filipendula ulmaria,
Fagopyrum esculentum 		C. albicans 31 125 Mature biofilm; XTT, crystal violet, and inverted light microscopy [68]
Salicylic acid
(phenolic acid)		 Salix sp.,
Filipendula ulmaria 		C. albicans 4000 2000 Mature biofilm; XTT, crystal violet, and inverted light microscopy [68]
Scopoletin
(cumarin)		 Mitracarpus frigidus,
Scopolia carniola 		C. tropicalis 50 50 Biofilm adhesion, formation, and mature biofilm; absorbance and digital scanning [77]
6-Shogaol
(phenylalkane)		 Zingiber officinale C. auris 32–64 16–64 Mature biofilm; crystal violet [78]
Tarolide
(sesquiterpene lactone)		 Laserpitium ochridanum,
L. zernyi 		C. albicans 400 1000 Mature biofilm; luminescence [43]
C. krusei 400 1000
Telekin
(sesquiterpene lactone)		 Carpesium macrocephalum,
Telekia speciose 		C. albicans >128 36 Biofilm formation and mature biofilm; XTT [67]
Terpinolene
(terpene)		 Cannabis sativa,
Citrus limon 		C. albicans 2000 4000 Mature biofilm; XTT, crystal violet, and inverted light microscopy [69]
5,7,3′,4′-Tetramethoxyflavone
(flavonoid)		 Psiadia punctulate,
Kaempferia parviflora 		C. albicans 100 40 Biofilm formation; crystal violet [79]
α-Thujone
(monotherpene)		 Artemisia absinthium,
Tanacetum vulgare 		C. albicans >4000 500 Mature biofilm; XTT, crystal violet, and inverted light microscopy [69]
Thymol
(phenol)		 Thymus vulgaris,
Trachyspermum copticum 		C. albicans 250 250 Mature biofilm; XTT, crystal violet, and inverted light microscopy [69]
1.56–50 3.12 Biofilm formation; absorbance, crystal violet, and scanning electron microscopy [26]
32–128 128 Biofilm adhesion and mature biofilm; XTT [80]
100–20,000 300–1250 Mature biofilm; XTT [71]
125 125–250 Biofilm formation and mature biofilm; XTT [81]
1200 5000–80,000 Mature biofilm; XTT [59]
C. tropicalis 1.56–50 12.5 Biofilm formation; absorbance, crystal violet, and scanning electron microscopy [26]
C. glabrata 100–20,000 300–1250 Mature biofilm; XTT [71]
C. parapsilosis 100–20,000 300–1250
Tn-AFP1
(protein)		 Trapa natans C. tropicalis 32 16 Mature biofilm; XTT [82]
5,6,8-Trihydroxy-7,4′
dimethoxy flavone
(flavonoid)		 Thymus membranaceus subsp. membranaceus,
Dodonaea viscosa var. angustifolia 		C. albicans 390 390 Biofilm formation and mature biofilm; MTT [83]
5(R)-Vanessine
(alkaloid)		 Waltheria indica C. albicans 32 16 Mature biofilm; XTT [63]
C. glabrata >32 16
C. krusei 32 16
C. parapsilosis >32 16
C. tropicalis >32 16
Vanillic acid
(phenolic acid)		 Angelica sinensis ,
Solanum tuberosum 		C. albicans >4000 4000 Mature biofilm; XTT, crystal violet, and inverted light microscopy [68]
Vanillin
(phenol)		 Vanilla planifolia C. albicans 1000 500 Mature biofilm; XTT, crystal violet, and inverted light microscopy [68]
Waltheriones
(alkaloid)		 Waltheria indica,
W.viscosissima 		C. albicans 4–32 8–32 Mature biofilm; XTT [63]
C. glabrata 32 or >32 8–32
C. krusei 16–32 or >32 8–32
C. parapsilosis 2–32 or >32 8–32
C. tropicalis 32 or >32 8–32
Warburganal
(sesquiterpene)		 Warburgia sp. C. albicans 4 4.5 Biofilm formation and mature biofilm; XTT and confocal laser microscopy [52]
C. glabrata 72–72.6 49.1–55.9
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Legend: MIC—minimal inhibitory concentration; XTT—reduction assay of 2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-5-[carbonyl(phenylamino)]-2H-tetrazolium hydroxide; MTT—reduction assay of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide [54,55].

In terms of activity, large differences were found, depending on the authors cited. Eugenol and thymol serve as good examples. Both compounds exhibited excellent activity in some studies (from 12.5 mg/L for eugenol [58] and 1.56 mg/L for thymol [26]), and in other studies, the activity was very poor (up to 80,000 for both [59]). These differences may be related, for example, to a different purity of the compound, a different fungal suspension density, or even to the use of other Candida strains with different sensitivities to chemical substances. A number of other factors, such as the type of culture medium, pH of the medium, incubation time, and temperature may likewise influence the antimicrobial activity [20].

According to the European Committee on Antimicrobial Susceptibility Testing (EUCAST), the antifungal clinical breakpoints are between 0.001 mg/L and 16 mg/L [60]. Using EUCAST guidelines in this review, the most active compounds that inhibit (>50%) Candida biofilm formation are lichochalcone A (from 0.2 mg/L) [61], thymol (from 3.12 mg/L) [26], dioscin (from 3.9 mg/L) [31], baicalein (from 4 mg/L) [62], warburganal (4.5 mg/L) [52], pterostilbene, waltheriones and riccardin D (both from 8 mg/L) [63,64,65], polygodial (10.8 mg/L) [52], cannabidiol and eugenol (both from 12.5 mg/L) [58,66], and ivalin (15.4 mg/L) [67]. It is interesting that monotherpenes, which represent the highest percentage of substances listed in Table 2, are not the most active compounds. The two larger groups with the best activity are phenolic compounds (thymol, pterostilbene, and eugenol), and sesquiterpene derivatives (warburganal, polygodial, and ivalin). Single compounds with the highest observed activity belong to chalconoids (lichochalcone A), steroidal saponins (dioscin), flavonoids (baicalein), alkaloids (waltheriones), macrocyclic bisbibenzyls (riccardin D), and cannabinoids (cannabidiol). Most of the compounds presented in Table 2 acted on biofilm formation and/or mature biofilm.

4. Conclusions

Plant preparations (essential oils and extracts) and pure compounds exhibit anti-biofilm activity against Candida species. Some of them are characterized by high activity in concentrations below 16 mg/L. Given this activity at relatively low concentrations, some may prove to be promising alternatives to antifungal drugs, especially in the cases of resistant or multiresistant strains of Candida. Moreover, the simple chemical structures involved and relative ease of extraction from natural sources warrant further research into the development of new, promising, and much-needed plant-based antifungals.

Acknowledgments

We are very grateful to Mark Stasiewicz for English language corrections.

Author Contributions

Conceptualization, T.M.K. and M.O.; methodology, T.M.K.; analysis of results, T.M.K. and M.O.; writing—original draft preparation, T.M.K., M.O., A.S.-M., H.W., and A.A.; writing—review and editing, T.M.K. and M.O.; supervision, T.M.K.; funding acquisition, T.M.K. and H.W. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

Footnotes

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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