Plant Preparations and Compounds with Activities against Biofilms Formed by Candida spp.
Department of Medical Microbiology, Poznań University of Medical Sciences, Wieniawskiego 3, 61-712 Poznań, Poland
Department of Biotechnology, Institute of Natural Fibres and Medicinal Plants, National Research Institute, Wojska Polskiego 71b, 60-630 Poznań, Poland; marcin.ozarowski@iwnirz.pl
Division of Perinatology and Women’s Diseases, Poznań University of Medical Sciences, Polna 33, 60-535 Poznań, Poland; asm@data.pl (A.S.-M.); hubertwolski@wp.pl (H.W.)
Laboratory of Molecular Biology in Division of Perinatology and Women’s Diseases, Poznań University of Medical Sciences, Polna 33, 60-535 Poznań, Poland
Department of Pharmacology and Phytochemistry, Institute of Natural Fibres and Medicinal Plants, National Research Institute, Kolejowa 2, 62-064 Plewiska, Poland
Division of Gynecology and Obstetrics, Podhale Multidisciplinary Hospital, Szpitalna 14, 34-400 Nowy Targ, Poland
Department of Botany, Breeding and Agricultural Technology of Medicinal Plants, Institute of Natural Fibres and Medicinal Plants, National Research Institute, Kolejowa 2, 62-064 Plewiska, Poland; artur.adamczak@iwnirz.pl
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.
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Keywords: Candida, biofilm, treatment, antifungals, natural compounds, essential oil, extract, minimal inhibitory concentration (MIC)
Article notes
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Received 2021 Mar 20; Accepted 2021 May 1; Collection date 2021 May.
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.
| 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] |
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).
| 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 |
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.
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
Footnote Group
References
Untitled section
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