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Review

Essential Oils in Respiratory Mycosis: A Review

by
Mónica Zuzarte
1,2,3,* and
Lígia Salgueiro
4,5
1
Faculty of Medicine, Coimbra Institute for Clinical and Biomedical Research (iCBR), University of Coimbra, 3000-548 Coimbra, Portugal
2
Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, 3000-548 Coimbra, Portugal
3
Clinical Academic Centre of Coimbra (CACC), 3000-548 Coimbra, Portugal
4
Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal
5
Faculty of Sciences and Technology, Department of Chemical Engineering, Chemical Process Engineering and Forest Products Research Centre (CIEPQPF), University of Coimbra, 3030-790 Coimbra, Portugal
*
Author to whom correspondence should be addressed.
Molecules 2022, 27(13), 4140; https://doi.org/10.3390/molecules27134140
Submission received: 6 June 2022 / Revised: 24 June 2022 / Accepted: 25 June 2022 / Published: 28 June 2022
(This article belongs to the Special Issue Natural Products: Therapeutic Properties and Beyond II)
Review Reports Versions Notes

Abstract

:
Respiratory mycosis is a major health concern, due to the expanding population of immunosuppressed and immunocompromised patients and the increasing resistance to conventional antifungals and their undesired side-effects, thus justifying the development of new therapeutic strategies. Plant metabolites, namely essential oils, represent promising preventive/therapeutic strategies due to their widely reported antifungal potential. However, regarding fungal infections of the respiratory tract, information is disperse and no updated compilation on current knowledge is available. Therefore, the present review aims to gather and systematize relevant information on the antifungal effects of several essential oils and volatile compounds against the main type of respiratory mycosis that impact health care systems. Particular attention is paid to Aspergillus fumigatus, the main pathogen involved in aspergillosis, Candida auris, currently emerging as a major pathogen in certain parts of the world, and Cryptococcus neoformans, one of the main pathogens involved in pulmonary cryptococcosis. Furthermore, the main mechanisms of action underlying essential oils’ antifungal effects and current limitations in clinical translation are presented. Overall, essential oils rich in phenolic compounds seem to be very effective but clinical translation requires more comprehensive in vivo studies and human trials to assess the efficacy and tolerability of these compounds in respiratory mycosis.

1. Introduction

Respiratory infections have increased over the past decades, becoming important causes of morbidity among immunocompromised and immunosuppressed patients and accounting for 4.3 million annual deaths worldwide [1]. Among these, fungal infections are underestimated, despite being responsible for mortality rates above 50% [2]. Although exposure to these respiratory pathogens occurs regularly during a lifetime, healthy individuals rarely develop symptomatic infections. However, in individuals with impaired defenses—for example, due to the use of chemotherapeutic and immunosuppressive agents, and antibiotics, or having prosthetic devices, grafts, burns, neutropenia or HIV—systemic life-threatening fungal infections may occur [3].
Overall, two main types of infections can occur: endemic (primary) or opportunistic. The first occur primarily in patients living or traveling in developing countries and, despite being mostly asymptomatic or causing mild infections, they account for huge health-care costs in these regions. Importantly, an exposure to high concentrations of inoculum or in patients with compromised immune defenses, life-threatening infections or the reactivation of latent foci may occur. The most common fungal infections include blastomycosis, coccidioidomycosis, histoplasmosis, paracoccidioidomycosis and sporotrichosis [4]. On the other hand, opportunistic infections generally occur in debilitated patients with impaired defense mechanisms and have a global distribution. These include aspergillosis, candidiasis, cryptococcosis, hyalohyphomycosis, mucormycosis, phaeohyphomycosis, and Pneumocystis pneumonia, with Aspergillus, Cryptococcus and Pneumocystis being the major pulmonary fungal pathogens capable of causing life-threatening invasive diseases [5]. In Section 2, a detailed characterization of these infections is presented with information regarding diagnosis, pathological symptoms and treatment.
The diagnosis of respiratory mycosis is quite difficult as it may present nonspecific symptoms and noninvasive diagnostic tests are poorly sensitive. Therefore, a combination of factors is frequently considered for an accurate diagnosis, namely clinical setting, chest imaging, and negative bacterial or viral studies [6]. To treat respiratory mycosis, several antifungals are available and include triazoles, echinocandins and formulations with amphotericin B. The first interfere with cytochrome P450 (CYP450) and lead to the inhibition of lanosterol, thus decreasing ergosterol synthesis and inhibiting cell-membrane development [7]. The most common are fluconazole and itraconazole, which are effective against Candida (except C. glabrata and C. krusei), Cryptococcus, Blastomyces, Histoplasma, and Coccidioides. The second-generation triazoles, including voriconazol and posaconazole, are also active against Aspergillus and Mucor. As these drugs undergo hepatic metabolism, drug–drug interactions may occur through the CYP450 system and side effects such as gastrointestinal disturbances, hepatotoxicity, headache, and rash have been reported [8]. Echinocandins induce osmotic instability and cell death in fungi, by compromising the synthesis of beta-(1,3) glucan synthase, an important component of their cell walls [7]. Examples of these antifungals are caspofungin, micafungin and anidulafungin, primarily used against Candida, Aspergillus and Pneumocystis. Treatment with echinocandins can cause rash, headache, fever, and chills [9]. Amphotericin B (AmB) also causes fungal death by creating channels or pores on the fungal cell membrane that leak cellular components [10]. Side-effects include weight loss, headache, fatigue, and phlebitis and most importantly nephrotoxicity that can be mitigated by using amphotericin B (AmB) formulations such as AmB colloidal dispersion and lipid formulations. Furthermore, combination therapy has also been considered as it tends to increase treatment efficacy, especially for drug-resistant fungal isolates [11]. Indeed the emergence of resistance is another challenging situation that has increased over the decades due to the use of azole fungicides for agricultural purposes [12]. Therefore, natural antifungal alternatives have emerged as promising agents to overcome resistance concerns and unwanted side-effects. The present review provides an updated compilation of the studies performed in the last 20 years based on a bibliographic search conducted using PubMed, Scopus and Google Scholar databases.

2. Types of Fungal Infections of the Respiratory Tract

Respiratory infections can be caused by the inhalation of spores from fungi that inhabit the environment. Although most people have been exposed to these pathogens, symptoms are rare in healthy individuals and infections are generally not transmitted between humans. However, in immunocompromised individuals these infections are of major concern being Aspergillus, Cryptococcus, Pneumocystis, and endemic fungi the major pulmonary fungal pathogens able to cause life-threatening invasive diseases [5]. Moreover, several risk factors, such as prolonged antibiotic use, hematologic malignancies and other immunocompromised states, worsen infection outcomes. Although the number of known fungi is relatively high—around 70,000—only 100 have been detected in respiratory infections with only a few being consistently considered pathogenic. Several of these fungi present dimorphism, with primary pathogens and Sporothrix schenckii, showing a morphological transformation in host tissues from a hyphal form to a yeast-like form (or spherule in the case of Coccidioides immitis). Contrarily, Candida albicans alters from blastoconidia to germ tubes that further develop into hyphae and Penicillium marneffei converts to transversely dividing sausage-shaped cells [13]. Moreover, many of these pathogens are capable of biofilm growth, forming highly organized communities that are resistant to antifungals and are responsible for recurrent infections [14]. Table 1 summarizes the main fungi responsible for relevant respiratory mycoses and points out for each pathogen (divided into endemic or opportunistic) the main source of infection, relevant pathological manifestations, diagnostic methods, and current therapy. The majority of information on some of the pathogens included in the table was based on the online textbook Microbiology, an OpenStax resource [15], the information on the remaining fungi being completed with other bibliographic sources such as clinical guidelines [16], centers for disease and health control [17] and professional manuals [18] available online.

3. In Vitro and In Vivo Models to Assess Antifungal Properties

The search for new antifungal agents involves in vitro susceptibility tests. Reference methods, namely the Clinical and Laboratory Standards Institute (CLSI) and the European Committee on Antimicrobial Susceptibility Testing (EUCAST) standard methods, are available enabling more practical, reliable, and reproducible protocols for antifungal susceptibility testing. Both resort to the broth microdilution method and assess the minimal inhibitory concentration (MIC) of an antifungal drug, which indicates the minimal drug concentration that inhibits fungal growth. Although these tests present some slight methodological differences, MICs are comparable [19]. Commercial antifungal susceptibility tests are also available. Examples include broth microdilution methods such as the SensititreTM or YeastOneTM that use color endpoints based on metabolic dyes such as AlamarBlue, incorporated into the growth media or agar-based methods, such as the Etest® and the automated system VITEK® 2 [20].
In addition to in vitro testing, pre-clinical animal models have enabled us to increase the knowledge on fungal infections and putative therapeutic strategies. In these assays it is important to consider the model species and its immune status, the route of infection, and the fungal strain used, as these aspects can impact experimental outcomes. Overall, inbred strains of laboratory mice are the most common models mainly due to their relatively low cost and the wide availability of immunological reagents. However, other vertebrates such as rats, guinea pigs, rabbits, and zebrafish have gained popularity [21]. Recently, the Galleria mellonella model has been one of the most used as it is inexpensive, easy to use, and does not require a dedicated infrastructure, the antifungal efficacy of the drug being estimated by fungal burden or mortality rate in infected and treated larvae [22]. To mimic respiratory mycosis, an intranasal or intratracheal injection of a liquid fungal suspension or the inhalation of dry fungal cells can be used. A catheter can be inserted beyond the vocal cords to facilitate intratracheal delivery of fungal cells and their dispersion into the pulmonary parenchyma may be enhanced by mechanical ventilation [23] or by using a microsprayer attached to the syringe tip [24]. Classical readouts include organ fungal burden and histopathology.

4. The Relevance of Essential Oils

Essential oils are mixtures of volatile compounds present in various organs of aromatic plants and obtained from the plant by hydrodistillation, steam distillation or dry distillation or, in the case of Citrus fruits, by a suitable mechanical process [25,26]. Essential oils generally present a strong odor and high lipophilicity, being primarily composed of terpenic compounds, such as monoterpenes and sesquiterpenes. In some cases, phenylpropanoids may also occur in high amounts and more rarely nitrogen and sulphur derivatives can be found. An important aspect to consider is their high chemical variability mainly due to environmental factors or genetic variations [27]. The latter may result in the expression of different metabolic pathways with significant variations in essential oils’ composition that justify the identification of chemotypes. To assure high quality of the commercialized essential oils, analytical guidelines published by several institutions, such as the European Pharmacopoeia, the International Standard Organization (ISO), and the World Health Organization (WHO), should be followed.
Essential oils play relevant natural roles primarily in plant defense and signaling processes and have been explored by several industries due to particular features such as aroma, taste and bioactive potential. Indeed, they are valuable raw materials in the pharmaceutical, agronomic, food, sanitary, cosmetic, and perfume industries [28]. In what concerns bioactive potential, several studies have highlighted the antifungal and anti-inflammatory potential of these compounds as reviewed elsewhere [29,30]. These properties are quite relevant in the context of respiratory mycosis as fungal infections are associated with acute inflammation, which exacerbates the infection and delays its eradication. Therefore, extracts or compounds that combine both antifungal and anti-inflammatory activities, at concentrations devoid of toxicity, emerge as suitable preventive/therapeutic agents.

4.1. Antifungal Effect of Essential Oils on Respiratory Mycosis

Essential oils and their volatile compounds have shown promising effects against fungi involved in infections of the respiratory tract. Overall, Aspergillus spp., Candida albicans, and Cryptococcus neoformans are by far the most assessed strains, with only a few studies being carried out on other relevant pathogens referred in Table 1. Next, a compilation of selected studies is presented, the assortment criteria being defined in each section.

4.1.1. Essential Oils in Aspergillosis

Regarding Aspergillus pathogens, A. fumigatus is the most ubiquitous strain and the major causal agent of aspergillosis, followed by A. flavus, A. niger, A. terreus, and A. nidulans [31]. Besides species diversity, several types of aspergillosis are known, namely pulmonary aspergillosis that generally develops in patients with underlying lung pathology; allergic bronchopulmonary aspergillosis, an allergic reaction that results from hypersensitivity to Aspergillus colonization and is generally exclusive to asthma and cystic fibrosis patients and invasive aspergillosis, the most severe type that occurs when the infection travels from the lungs into the bloodstream [32]. As A. fumigatus is the main pathogen involved in aspergillosis, a compilation of the studies showing minimal inhibitory (MIC) or minimal fungicidal/lethal concentrations (MFC/MLC) is presented in Table 2. Only essential oils presenting MICs lower than 10 mg/mL were considered, being the plant name, part of the plant used to obtain the essential oils and antifungal effect highlighted, whenever this information was available in the original study. Broader studies, gathering more than three species, are not included in the table, and are discussed next. Furthermore, since only a few studies assessed a possible mechanism of action underlying these effects, this topic is discussed in Section 4.2.
As previously mentioned, some studies have included several essential oils. For example, in a study involving fifteen species from the Asteraceae family, only Achyrocline alata and Baccharis latifolia essential oils were effective against A. fumigatus (geometric mean MIC value of 78.7 and 157.4 µg/mL, respectively) [62]. Moreover, in some cases both essential oil direct contact or vapor phase are assessed, thus foreseeing different modes of administration and distinct applications. For example, resorting to these two strategies, the essential of Eugenia caryophyllata, Lavandula angustifolia, Origanum vulgare, Salvia sclarea, Thuja plicata and Thymus vulgaris were assessed, being Origanum vulgare essential oil the most effective, through direct contact, with a MIC value of 0.025%. However, the volatile vapor of 0.075% of the majority of the oils was also able to exert a fungicidal effect on A. fumigatus, proving that these oils can be used, for example, for environmental disinfection [63].
Synergistic studies between essential oils and isolated compounds or essential oils with conventional antifungals are also relevant, thus reducing the effective dose needed and improving therapeutic outcomes [64]. Indeed, a chessboard assay using twenty-five essential oils showed that a combination of Cymbopogon citratus and Thymus serpyllum oils was the most potent against A. fumigatus (fractional inhibitory concentration index -FICI- of 0.1875; with a total synergistic effect considered for values ≤ 0.5) [65]. Additionally, Thymus vulgaris essential oils and thymol showed significant levels of synergistic interaction with fluconazole presenting an FICI value of 0.187 [40].
Moreover, mixed microbial infections are known to cause significant health care burdens and are commonly found in patients with chronic infections. Therefore, some studies have also considered this reality by assessing the polymicrobial antibiofilm effect of essential oils. A study carried out by Pekmezovic and colleagues addressed this ability using selected Citrus essential oils and showed that 10 mg/L of the oils were able to both inhibit a mixed biofilm formation composed of Pseudomonas aeruginosa and Aspergillus fumigatus and affect quorum sensing [66].
Finally, in vivo validations are of utmost importance but are quite sparse regarding respiratory mycosis. A pre-clinical study confirmed the potential of Leptospermum petersonii essential oil by showing a significant reduction of fungal infection in the lungs of animals that completed the treatment regimen and the effect was strikingly superior to that reported for conventional antifungal drugs [48].
Regarding the potential of isolated compounds, very few studies have been performed. Once again phenolic compounds stand out as very effective, namely eugenol—MIC = 250 ug/mL [49], thymol—MIC = 192 μg/mL [40] and carvacrol—MIC = 0.16 µL/mL [51]. Indeed, this could explain the excellent activity of some of the essential oils pointed out above such as Thymus vulgaris (rich in thymol) and Lavandula multifida (with high amounts of carvacrol). Besides phenolic compounds, other essential oils constituents such as safrole have shown very effective antifungal abilities against A. fumigatus, with a MIC of 39.1 µg/mL [42]. Interestingly, although the essential oil obtained from the roots of Cinnamomum camphora had a high concentration of this compound (57.6%), the antifungal potential of the whole extract was not so prominent (MIC = 312.5 µg/mL), thus showing that, in some cases, antagonistic effects may also take place between different compounds present in the mixture. Additionally, 1,8-cineole, a compound widely found in many essential oils, showed promising effects with a MIC value of 156.3 µg/mL [42].

4.1.2. Essential Oils in Respiratory Candidiasis

Candida infections are quite difficult to detect as Candida spp. inhabit the normal microflora of the skin, oral cavity, gastrointestinal mucosa, respiratory tract, and genitourinary tract [67]. Moreover, despite covering more than two-thirds of fungal infections, invasive candidiasis (defined as the presence of Candida in the blood—candidemia—or firmly established Candida infections) rarely manifest as Candida pneumonia and antifungal treatments in these cases is a matter of ongoing debate [68]. Nevertheless, Candida albicans, C. glabrata, C. tropicalis, C. parapsilosis and C. krusei have been pointed out as the most prevalent strains in invasive candidiasis. Since several reviews have largely covered the antifungal potential of essential oils on these pathogens [69,70,71,72,73], we now focus on a once considered rare species, Candida auris, that is currently emerging as a major pathogen in certain parts of the world. C. auris infections are difficult to treat as this pathogen does not respond to conventional antifungal drugs. This fungus also presents a high risk of transmission as it persists on several equipment and medical devices [74]. Importantly, some essential oils have shown promising antifungal potential against this species. Table 3 compiles this information by pointing out the plant species, part of the plant used to obtain the essential oil and its main compounds, whenever referred to in the original study. The antifungal potential of the essential oil is also highlighted, as well as the mechanism of action underlying the observed effect, if assessed.
Although C. auris is an emergent species, several studies have already shown the potential of essential oils as effective antifungal agents, as highlighted in Table 3. Nevertheless, as different susceptibility tests are used and units lack uniformity among studies, it is quite difficult to perform comparisons between studies and understand which essential oil is the most effective. Even so, it seems that essential oils rich in phenolic compounds exert a more potent inhibitory effect. Indeed, the phenolic compound carvacrol assessed alone has already shown promising effects. A median MIC of 125 µg/mL was reported as well as synergistic and additive effects in combination with the conventional antifungals fluconazole, amphotericin B, nystatin and caspofungin [82].

4.1.3. Essential Oils in Cryptococcosis

Pulmonary cryptococcosis, contrarily to cryptococcal meningitis, remains underdiagnosed mainly due to limitations in diagnostic tools. Indeed, the infection presents similar clinical and radiological features to lung cancer, pulmonary tuberculosis, bacterial pneumonia, and other pulmonary mycoses. The genus Cryptococcus consists of more than 70 species, the two main human pathogens being C. neoformans and C. gattii [83]. Several studies have also pointed out the antifungal potential of essential oils, mainly for C. neoformans. Table 4 compiles these studies referring to the plant name, part of the plant used to obtain the essential oils, and antifungal effect. Since the mechanisms of action underlying these effects are poorly explored, this topic will be discussed collectively in Section 4.2.
Besides the studies referred to in Table 4, others were performed gathering a higher number of species, with bigger data approaches enabling more extensive analysis. For example, using this approach, eighty-two essential oils were analyzed, with fifteen being highlighted as very potent (MIC ≤ 100 μg/mL), and from these Cedrus atlantica standing out as the most effective, with a MIC value of 20 μg/mL [116]. In another extensive study, the antifungal potential of sixty commercially-available essential oils was also assessed, with Cinnamomum cassia, C. zeylanicum, Coriandrum sativum, Pogostemon cablin, Santalum album, S. austrocaledonicum, S. paniculatum and Vetiveria zizanoides being very effective (MIC = 20 µg/mL) [117].
Some studies also resort to ethnopharmacological evidence and tend to assess the potential of essential oils based on their traditional uses, thus recovering relevant knowledge that tends to be lost over time. For example, the study carried out by Lawson and colleagues considered a specific group of plants from the Asteraceae family used in Cherokee and other Native American traditional medicines, and showed a very potent effect of Eupatorium serotinum essential oil against Cryptococcus neoformans with a MIC value of 78 μg/mL [118].
Regarding synergistic studies between essential oils and conventional drugs, interesting results against Cryptococcus neoformans have also been reported. For example, Scalas and colleagues, through checkerboard testing and isobolographic analysis, showed synergistic effects (FICI ≤ 0.5) between itraconazole and Origanum vulgare, Pinus sylvestris or Thymus vulgaris essential oils. Importantly, a synergistic effect was also observed with itraconazole and Thymus vulgaris essential oil (chemotype: thymol 26.52%; carvacrol 7.85%) on an azole not susceptible strain of Cryptococcus neoformans, thus confirming the potential of essential oils as cost-effective adjuvants in antifungal therapy [119]. Using similar methodology, the combination of Mentha x piperita essential oil with itraconazole also exerted a synergistic effect (FICI ≤ 0.5), with a decrease in the MIC. Nevertheless, on the azole-resistant strain, the binary combination of itraconazole and the oil yielded additive effects [97]. Furthermore, the combination of Ocimum basilicum var. Maria Bonita (a genetically improved cultivar) essential oil with fluconazole enhanced the antifungal activity, especially against the resistant strain of Cryptococcus neoformans, with MIC being reduced from 1250 μg/mL to 625 μg/mL [120].
Combinations between essential oils have also shown positive effects on Cryptococcus neoformans. For example, combining the essential oils of Boswellia rivae, B. neglecta and B. papyrifera with Commiphora guidotti or C. myrrha oils displayed synergistic, additive and noninteractive properties with MICs ranging from 0.5–5.3 mg/mL [121].
Regarding isolated compounds, several studies have been performed, showing that the most potent compounds against Cryptococcus neoformans were (E)-Dec-2-enal with a MIC of 25.65 ug/mL [85], α-pinene with a MIC value of 0.07 mg/mL [113], and (R)-(+)-limonene with a fungicidal effect at 0.08µL/mL [112]. These effects may explain the potential of Aristolochia delavayi essential oil, with high amounts of (E)-dec-2-enal [85], and Bupleurum rigidum subsp. paniculatum and Thapsia villosa rich in α-pinene [88,112]. Geraniol also showed promising effects with a study pointing out a MIC of 76 µg/mL [120]; nevertheless in other studies, the MICs were quite distinct (MIC80 = 128 µg/mL [122] and MIC = 0.32 μL/mL [61]). Variability between MIC values can occur mainly due to variations between laboratories and strains [123]. Other compounds showed some antifungal potential but to a less extent, namely linalool (MIC = 5 μL/mL) and terpinen-4-ol (MIC = 1.25 μL/mL) [61], sabinene (MIC = 0.32μL/mL) and cis-β-ocimene (MIC = 0.16–0.32μL/mL) [102], methyleugenol (MIC= 0.32 μL/mL) [112], and carvacrol (MIC= 0.16 μL/mL) [51].

4.1.4. Essential Oils on Other Respiratory Infections

Concerning other fungal strains involved in respiratory mycosis, namely those referred to in Table 1, in vitro studies have been performed, although to a much lesser extent. Table 5 compiles these studies and points out their main findings.
Regarding isolated compounds, several studies have been performed. Overall, farnesol, a sesquiterpenic compound, and terpinene-4-ol, a terpene alcohol, were the most assessed and showed very promising effects. For example, farnesol was tested against Coccidioides posadasii—MIC = 0.002–0.01 mg/L [127], Histoplasma capsulatum var. capsulatum—MIC = 0.008–0.003 µM [128] and Sporothrix schenckii—MIC = 0.003 to 0.222 μg/mL [129]. Importantly, in the first two pathogens, synergistic effects with amphotericin B, itraconazole, voriconazole and caspofungin or itraconazole, respectively were observed [127,128], thus confirming its potential as an adjuvant in fungal infections. On the other hand, terpinene-4-ol was tested against Sporothrix schenckii (MIC = 4–32 mg/L) and was able to decrease its cellular ergosterol content. In combination with itraconazole or terbinafine, it also exerted a synergistic effect [130]. Furthermore, this compound was also effective against Coccidioides posadasii (MIC = 350–1420 μg/mL) and Histoplasma capsulatum [MIC = 20–1420 μg/mL (filamentous phase) and 40–350 μg/mL (yeast phase)], although to a lesser extent [131].
Other compounds have also been tested, such as the monoterpene p-cymene (MIC = 1024 μg/mL) and the phenolic compound thymol (MIC = 128–256 μg/mL), against Rhizopus oryzae [124]. Furthermore, the sesquiterpene dialdehyde polygodial was also very effective against Penicillium marneffei with a MIC value of 3.3 μg/mL [132]. These studies, although still limited in number, show that other fungal pathogens are being considered for antifungal susceptibility testing, besides the gold standard strains, thus opening new avenues for the development of new preventive/therapeutic strategies.

4.2. Mechanism of Action Underlying Essential Oils Antifungal Effects

The majority of the in vitro studies performed tend to identify the MIC and MLC/MFC of the volatile extract/compound and in some cases, the putative mechanism of action underlying the antifungal effect. Indeed, several methods have been proposed to elucidate the target site or the mechanism of action of the essential oils, in fungal cells [133]. Generally, mechanistic studies are performed on Candida albicans and the main effects considered are biofilm disruption, cell morphology and plasma membrane integrity. In less extent mitochondrial enzymes, reactive oxygen species (ROS) and gene expression are also assessed. Next, studies performed on other pathogens rather than Candida albicans are highlighted, namely for biofilm and cell wall/membrane integrity.
Biofilms are important virulence factors for pathogenic fungi naturally formed when fungi change from a planktonic to a sessile state and attach to surfaces and to each other, being involved and protected by a polymeric extracellular matrix. The fungi also secrete quorum-sensing molecules that play a relevant role in fungal resistance and pathogenicity [134] and, therefore, constitute a very promising therapeutic target.
Kumari and colleagues carried out a study using several compounds present in essential oils and confirmed their anti-biofilm effect on Cryptococcus laurentii and Cryptococcus neoformans in the following order: thymol > carvacrol > citral > eugenol = cinnamaldehyde > menthol. Indeed, for the most effective compounds, a potent effect on biofilm morphology was confirmed by scanning electron microscopy and confocal laser scanning microscopy that showed the absence of extracellular polymeric matrix, reduction in cellular density and alteration in the surface morphology of biofilm cells [122].
Other relevant therapeutic targets that are highly assessed are the structural elements of fungi cell walls and membranes, as their inhibition can affect cell wall maturation, septum formation, and bud ring formation, by damaging cell division and cell growth. Essential oils are able to disrupt the cell wall, leading to cytoplasm leakage and compromise fungi membrane permeability and fluidity by altering its properties and compromising membrane-associated functions. Indeed, morphological and ultrastructural alterations were observed in Aspergillus fumigatus exposed to Cuminum cyminum, Nigella sativa and Ziziphora clinopodioides essential oil that interfered with the enzymes involved in cell wall synthesis, caused high vacuolation of the cytoplasm, detachment of the fibrillar layer of cell wall, and plasma membrane disruption. Additionally, disorganization of nuclear and mitochondrial structures was observed [44]. Similarly, Leptospermum petersonii essential oil disturbed Aspergillus fumigatus cell membrane with alterations observed in hyphal morphology, susceptibility of spheroplasts and uptake of propidium iodide following exposure to the oil [48]. Regarding isolated compounds, eugenol reduced the cell diameter and capsule size of Cryptococcus gattii and C. neoformans. The compound was also able to increase the levels of ROS, leading to increased lipid peroxidation, mitochondrial membrane depolarization and reduction of lysosomal integrity in these fungi [135]. Another relevant target for essential oils is ergosterol, a compound present in the fungal cell membrane whose biosynthesis can be altered by disturbing sterol biosynthetic pathways. Importantly, the absence or reduced presence of ergosterol in fungal membranes results in osmotic and metabolic instability of the fungal cell, compromising reproduction and infectious activity [136]. Indeed, it was shown that Thymus vulgaris essential oil and its main compound, thymol, were effective against Rhizopus oryzae due to their interaction with ergosterol, thus supporting their use in the management of mucormycosis [124].

5. Translation to the Clinic: Limitations and Future Perspectives

Studies comparing different treatments for respiratory mycosis, namely cryptococcal meningitis, candidemia, endemic mycoses, and invasive aspergillosis, are among the most cited clinical trials and are very relevant for the development of treatment guidelines for these infections [137]. Nevertheless, regarding essential oils as anti-infective agents, clinical trials are lacking. Moreover, essential oils present several features such as hydrophobicity, instability, high volatility, and possible toxicity that compromise their use. Therefore, to overcome these limitations, encapsulation resorting to delivery systems, namely lipid-based carriers, have been developed to stabilize these compounds, improve the shelf-life of the formulated products and prolong the biological effect of the active molecules [138]. For example, Lavandula angustifolia essential oil encapsulated in liposomes was effective against persistent biofilms of Candida auris [78] while Lippia sidoides essential oil encapsulated in nanostructured lipid carriers showed anti-Candida auris potential and low toxicity, suggesting a new strategy to overcome multidrug-resistant pathogens [79]. On the other hand, due to their volatility, essential oils can easily reach the upper and lower parts of the respiratory tract via active or passive inhalation. In the first case, an inhalation device is needed for the patients to directly inhale the volatile compounds whereas in the latter, heating, vaporization or ventilation is used to deliver these compounds to the environment [139]. Interestingly, over the last years, several patents on portable inhalation devices have been registered and have been shown to be suitable delivery systems for these volatile compounds. Another possible form of administration resorts to patches, the volatiles being released to the skin and/or inhaled by the patient [140].

6. Final Remarks

The present review provides, for the first time, an updated compilation of relevant information on the antifungal potential of essential oils and their volatile compounds on respiratory mycosis. Overall, our bibliographic search showed that the majority of the studies are performed on strains involved in opportunistic infections, namely aspergillosis, candidiasis and cryptococcosis, with the present review focusing on strains involved in life-threatening invasive diseases such as Aspergillus fumigatus and Cryptococcus neoformans and relevant emergent strains such as Candida auris. Moreover, it is quite evident that essential oils rich in phenolic compounds, namely thymol and carvacrol, are very effective, and therapeutic improvements can be achieved by combining essential oils and/or their volatile compounds with conventional antifungal drugs. Furthermore, several administration strategies and devices have been designed to effectively deliver these volatile compounds but clinical translation still requires in vivo validations and human trials to confirm the efficacy and tolerability of these extracts/compounds in respiratory mycosis.

Author Contributions

Conceptualization, M.Z. and L.S.; methodology, M.Z. and L.S.; validation, M.Z. and L.S.; writing—original draft preparation, M.Z.; writing—review and editing, L.S.; funding acquisition, M.Z. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by FCT and Fundação La Caixa under the project: PLANTS4AGEING.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Chowdhary, A.; Agarwal, K.; Meis, J.F. Filamentous fungi in respiratory infections. What lies beyond aspergillosis and mucormycosis? PLoS Pathog. 2016, 12, e1005491. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  2. Brown, G.D.; Denning, D.W.; Gow, N.A.R.; Levitz, S.M.; Netea, M.G.; White, T.C. Hidden Killers: Human fungal infections. Sci. Transl. Med. 2012, 4, 165rv13. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  3. Ravikumar, S.; Win, M.S.; Chai, L.Y.A. Optimizing outcomes in immunocompromised hosts: Understanding the role of immunotherapy in invasive fungal diseases. Front. Microbiol. 2015, 6, 1322. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  4. Di Mango, A.L.; Zanetti, G.; Penha, D.; Menna Barreto, M.; Marchiori, E. Endemic pulmonary fungal diseases in immunocompetent patients: An emphasis on thoracic imaging. Expert. Rev. Respir. Med. 2019, 13, 263–277. [Google Scholar] [CrossRef]
  5. Li, Z.; Lu, G.; Meng, G. Pathogenic fungal infection in the lung. Front. Immunol. 2019, 10, 1524. [Google Scholar] [CrossRef] [Green Version]
  6. Miller, A.S.; Wilmott, R.W. The Pulmonary Mycoses. In Kendig’s Disorders of the Respiratory Tract in Children; Elsevier: Amsterdam, The Netherlands, 2019; pp. 507–527.e3. [Google Scholar] [CrossRef]
  7. Boucher, H.W.; Groll, A.H.; Chiou, C.C.; Walsh, T.J. Newer systemic antifungal agents. Drugs 2004, 64, 1997–2020. [Google Scholar] [CrossRef]
  8. Limper, A.H.; Knox, K.S.; Sarosi, G.A.; Ampel, N.M.; Bennett, J.E.; Catanzaro, A.; Davies, S.F.; Dismukes, W.E.; Hage, C.A.; Marr, K.A.; et al. An official American thoracic society statement: Treatment of fungal infections in adult pulmonary and critical care patients. Am. J. Respir. Crit. Care Med. 2011, 183, 96–128. [Google Scholar] [CrossRef] [Green Version]
  9. Cook, S.; Confer, J. Assessment and treatment of fungal lung infections. US Pharm. 2011, 36, HS-17-HS-24. [Google Scholar]
  10. Moen, M.D.; Lyseng-Williamson, K.A.; Scott, L.J. Liposomal amphotericin B. Drugs 2009, 69, 361–392. [Google Scholar] [CrossRef]
  11. Chang, Y.-L.; Yu, S.-J.; Heitman, J.; Wellington, M.; Chen, Y.-L. New facets of antifungal therapy. Virulence 2017, 8, 222–236. [Google Scholar] [CrossRef] [Green Version]
  12. Chowdhary, A.; Kathuria, S.; Xu, J.; Meis, J.F. Emergence of azole-resistant Aspergillus fumigatus strains due to agricultural azole use creates an increasing threat to human health. PLoS Pathog. 2013, 9, e1003633. [Google Scholar] [CrossRef]
  13. Walsh, T.J.; Dixon, D.M. Spectrum of mycoses. Med. Microbiol. 1996, 75, 919–925. Available online: http://www.ncbi.nlm.nih.gov/pubmed/21413276 (accessed on 1 June 2022).
  14. Desai, J.V.; Mitchell, A.P.; Andes, D.R. Fungal biofilms, drug resistance, and recurrent infection. Cold Spring Harb. Perspect Med. 2014, 4, a019729. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  15. Parker, N.; Schneegurt, M.; Thi Tu, A.-H.; Lister, P.; Forster, B.M. Microbiology. 2016. Available online: https://openstax.org/books/microbiology/pages/22-4-respiratory-mycoses (accessed on 1 June 2022).
  16. Clinical info HIV gov. Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents with HIV. Available online: https://clinicalinfo.hiv.gov/en/guidelines/adult-and-adolescent-opportunistic-infection/talaromycosis-formerly-penicilliosis (accessed on 1 June 2022).
  17. Centers for Disease Control and Prevention. Available online: https://www.cdc.gov/ (accessed on 1 June 2022).
  18. MSD Manual for the Professional. Available online: https://www.msdmanuals.com/en-pt/professional) (accessed on 1 June 2022).
  19. Pfaller, M.A.; Espinel-Ingroff, A.; Boyken, L.; Hollis, R.J.; Kroeger, J.; Messer, S.A.; Tendolkar, S.; Diekema, D.J. Comparison of the broth microdilution (BMD) method of the European Committee on Antimicrobial Susceptibility Testing with the 24-Hour CLSI BMD method for testing susceptibility of Candida species to fluconazole, posaconazole, and voriconazole by use of epidemiological cut-off values. J. Clin. Microbiol. 2011, 49, 845–850. [Google Scholar] [CrossRef] [Green Version]
  20. Sanguinetti, M.; Posteraro, B. Susceptibility testing of fungi to antifungal drugs. J. Fungi 2018, 4, 110. [Google Scholar] [CrossRef] [Green Version]
  21. Hohl, T.M. Overview of vertebrate animal models of fungal infection. J. Immunol. Methods 2014, 410, 100–112. [Google Scholar] [CrossRef] [Green Version]
  22. Jemel, S.; Guillot, J.; Kallel, K.; Botterel, F.; Dannaoui, E. Galleria mellonella for the evaluation of antifungal efficacy against medically important fungi, a narrative review. Microorganisms 2020, 8, 390. [Google Scholar] [CrossRef] [Green Version]
  23. Hasenberg, M.; Köhler, A.; Bonifatius, S.; Jeron, A.; Gunzer, M. Direct observation of phagocytosis and NET-formation by neutrophils in infected lungs using 2-photon microscopy. J. Vis. Exp. 2011, 52, e2659. [Google Scholar] [CrossRef] [Green Version]
  24. Kelly, M.M.; McNagny, K.; Williams, D.L.; van Rooijen, N.; Maxwell, L.; Gwozd, C.; Mody, C.H.; Kubes, P. The lung responds to zymosan in a unique manner independent of Toll-like receptors, complement, and dectin-1. Am. J. Respir. Cell Mol. Biol. 2008, 38, 227–238. [Google Scholar] [CrossRef]
  25. ISO 9235. Aromatic Natural Raw Materials—Vocabulary. ISO: Geneva, Switzerland, 2013.
  26. Council of Europe. Directorate for the Quality of Medicines & HealthCare of the Council of Europe, 7th ed.; European Pharmacopoeia: Strasbourg, France, 2010. [Google Scholar]
  27. Figueiredo, A.C.; Barroso, J.G.; Pedro, L.G.; Johannes, S.J.C. Factors affecting secondary metabolite production in plants: Volatile components and essential oils. Flavour Fragr. J. 2008, 23, 213–226. [Google Scholar] [CrossRef]
  28. Irshad, M.; Ali Subhani, M.; Ali, S.; Hussain, A. Biological importance of essential oils. In Essential Oils-Oils of Nature; IntechOpen: London, UK, 2020. [Google Scholar] [CrossRef] [Green Version]
  29. Wińska, K.; Mączka, W.; Łyczko, J.; Grabarczyk, M.; Czubaszek, A.; Szumny, A. Essential oils as antimicrobial agents—Myth or real alternative? Molecules 2019, 24, 2130. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  30. Lucca, L.G.; Romão, P.R.T.; Vignoli-Silva, M.; da Veiga-Junior, V.F.; Koester, L.S. In vivo acute anti-inflammatory activity of essential oils: A review. Mini-Rev. Med. Chem. 2021, 21, 1495–1515. [Google Scholar] [CrossRef] [PubMed]
  31. Sugui, J.A.; Kwon-Chung, K.J.; Juvvadi, P.R.; Latge, J.-P.; Steinbach, W.J. Aspergillus fumigatus and related species. Cold Spring Harb. Perspect. Med. 2015, 5, a019786. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  32. El-Baba, F.; Gao, Y.; Soubani, A.O. Pulmonary aspergillosis: What the generalist needs to know. Am. J. Med. 2020, 133, 668–674. [Google Scholar] [CrossRef] [PubMed]
  33. Falconieri, D.; Piras, A.; Porcedda, S.; Marongiu, B.; Gonçalves, M.J.; Cabral, C.; Cavaleiro, C.; Salgueiro, L. Chemical composition and biological activity of the volatile extracts of Achillea millefolium. Nat. Prod. Commun. 2011, 6, 1527–1530. [Google Scholar] [CrossRef] [Green Version]
  34. Joshi, R.K. Acorus calamus Linn.: Phytoconstituents and bactericidal property. World J. Microbiol. Biotechnol. 2016, 32, 164. [Google Scholar] [CrossRef]
  35. Li, R.; Wang, Y.-F.; Sun, Q.; Hu, H.-B. Chemical composition and antimicrobial activity of the essential oil from Allium hookeri consumed in Xishuangbanna, southwest China. Nat. Prod. Commun. 2014, 9, 863–864. [Google Scholar] [CrossRef] [Green Version]
  36. Marongiu, B.; Piras, A.; Porcedda, S.; Falconieri, D.; Maxia, A.; Frau, M.A.; Gonçalves, M.J.; Cavaleiro, C.; Salgueiro, L. Isolation of the volatile fraction from Apium graveolens L. (Apiaceae) by supercritical carbon dioxide extraction and hydrodistillation: Chemical composition and antifungal activity. Nat. Prod. Res. 2013, 27, 1521–1527. [Google Scholar] [CrossRef]
  37. Joshi, R.K. Volatile composition and antimicrobial activity of the essential oil of Artemisia absinthium growing in Western Ghats region of North West Karnataka. India Pharm. Biol. 2013, 51, 888–892. [Google Scholar] [CrossRef]
  38. Dehghani Bidgoli, R. Chemical composition of essential oil and antifungal activity of Artemisia persica Boiss. Iran. J. Food Sci. Technol. 2021, 58, 1313–1318. [Google Scholar] [CrossRef]
  39. Salleh, W.M.N.H.W.; Ahmad, F.; Yen, K.H. Chemical compositions and biological activities of the essential oils of Beilschmiedia madang Blume (Lauraceae). Arch. Pharm. Res. 2015, 38, 485–493. [Google Scholar] [CrossRef] [PubMed]
  40. Khan, M.S.A.; Ahmad, I.; Cameotra, S.S. Carum copticum and Thymus vulgaris oils inhibit virulence in Trichophyton rubrum and Aspergillus spp. Braz. J. Microbiol. 2014, 45, 523–531. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  41. Carev, I.; Ruščić, M.; Skočibušić, M.; Maravić, A.; Siljak-Yakovlev, S.; Politeo, O. Phytochemical and cytogenetic characterization of Centaurea solstitialis L. (Asteraceae) from Croatia. Chem. Biodivers. 2017, 14, e1600213. [Google Scholar] [CrossRef] [PubMed]
  42. Poudel, D.K.; Rokaya, A.; Ojha, P.K.; Timsina, S.; Satyal, R.; Dosoky, N.S.; Satyal, P.; Setzer, W.N. The Chemical profiling of essential oils from different tissues of Cinnamomum camphora L. and their antimicrobial activities. Molecules 2021, 26, 5132. [Google Scholar] [CrossRef]
  43. Taha, A.M.; Eldahshan, O.A. Chemical characteristics, antimicrobial, and cytotoxic activities of the essential oil of Egyptian Cinnamomum glanduliferum Bark. Chem. Biodivers. 2017, 14, e1600443. [Google Scholar] [CrossRef]
  44. Khosravi, A.R.; Minooeianhaghighi, M.H.; Shokri, H.; Emami, S.A.S.M.A.; Asili, J. The potential inhibitory effect of Cuminum cyminum, Ziziphora clinopodioides and Nigella sativa essential oils on the growth of Aspergillus fumigatus and Aspergillus. Braz. J. Microbiol. 2011, 42, 216–224. [Google Scholar] [CrossRef] [Green Version]
  45. Maxia, A.; Marongiu, B.; Piras, A.; Porcedda, S.; Tuveri, E.; Gonçalves, M.J.; Cavaleiro, C.; Salgueiro, L. Chemical characterization and biological activity of essential oils from Daucus carota L. subsp. carota growing wild on the Mediterranean coast and on the Atlantic coast. Fitoterapia 2009, 80, 57–61. [Google Scholar] [CrossRef]
  46. Raimundo, K.F.; Bortolucci, W.d.C.; Glamočlija, J.; Soković, M.; Gonçalves, J.E.; Linde, G.A.; Gazim, Z.C. Antifungal activity of Gallesia integrifolia fruit essential oil. Braz. J. Microbiol. 2018, 49, 229–235. [Google Scholar] [CrossRef]
  47. Cabral, C.; Francisco, V.; Cavaleiro, C.; Gonçalves, M.J.; Cruz, M.T.; Sales, F.; Batista, M.T.; Salgueiro, L. Essential oil of Juniperus communis subsp. alpina (Suter) Čelak needles: Chemical composition, antifungal activity and cytotoxicity. Phyther. Res. 2012, 26, 1352–1357. [Google Scholar] [CrossRef]
  48. Hood, J.R.; Burton, D.M.; Wilkinson, J.M.; Cavanagh, H.M.A. The effect of Leptospermum petersonii essential oil on Candida albicans and Aspergillus fumigatus. Med. Mycol. 2010, 48, 922–931. [Google Scholar] [CrossRef] [Green Version]
  49. Mesa-Arango, A.C.; Montiel-Ramos, J.; Zapata, B.; Durán, C.; Betancur-Galvis, L.; Stashenko, E. Citral and carvone chemotypes from the essential oils of Colombian Lippia alba (Mill.) N.E. Brown: Composition, cytotoxicity and antifungal activity. Mem. Inst. Oswaldo Cruz. 2009, 104, 878–884. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  50. Zuzarte, M.; Gonçalves, M.J.; Cruz, M.T.; Cavaleiro, C.; Canhoto, J.; Vaz, S.; Pinto, E.; Salgueiro, L. Lavandula luisieri essential oil as a source of antifungal drugs. Food Chem. 2012, 135, 1505–1510. [Google Scholar] [CrossRef] [PubMed]
  51. Zuzarte, M.; Vale-Silva, L.; Gonçalves, M.J.; Cavaleiro, C.; Vaz, S.; Canhoto, J.; Pinto, E.; Salgueiro, L. Antifungal activity of phenolic-rich Lavandula multifida L. essential oil. Eur. J. Clin. Microbiol. Infect. Dis. 2012, 31, 1359–1366. [Google Scholar] [CrossRef]
  52. Zuzarte, M.; Gonçalves, M.J.; Cavaleiro, C.; Dinis, A.M.; Canhoto, J.M.; Salgueiro, L.R. Chemical composition and antifungal activity of the essential oils of Lavandula pedunculata (Miller) Cav. Chem. Biodivers. 2009, 6, 1283–1292. [Google Scholar] [CrossRef] [PubMed]
  53. Zuzarte, M.; Gonçalves, M.J.; Cavaleiro, C.; Cruz, M.T.; Benzarti, A.; Marongiu, B.; Maxia, A.; Piras, A.; Salgueiro, L. Antifungal and anti-inflammatory potential of Lavandula stoechas and Thymus herba-barona essential oils. Ind. Crops Prod. 2013, 44, 97–103. [Google Scholar] [CrossRef]
  54. Zuzarte, M.; Gonçalves, M.J.; Cavaleiro, C.; Canhoto, J.; Vale-Silva, L.; Silva, M.J.; Pinto, E.; Salgueiro, L. Chemical composition and antifungal activity of the essential oils of Lavandula viridis L’Hér. J. Med. Microbiol. 2011, 60, 612–618. [Google Scholar] [CrossRef] [Green Version]
  55. Hammer, K.A. In vitro activity of Melaleuca alternifolia (tea tree) oil against dermatophytes and other filamentous fungi. J. Antimicrob. Chemother. 2002, 50, 195–199. [Google Scholar] [CrossRef]
  56. Bouzabata, A.; Cabral, C.; Gonçalves, M.J.; Cruz, M.T.; Bighelli, A.; Cavaleiro, C.; Casanova, J.; Tomi, F.; Salgueiro, L. Myrtus communis L. as source of a bioactive and safe essential oil. Food Chem. Toxicol. 2015, 75, 166–172. [Google Scholar] [CrossRef]
  57. Li, R.; Yang, J.-J.; Wang, Y.-F.; Sun, Q.; Hu, H.-B. Chemical composition, antioxidant, antimicrobial and anti-inflammatory activities of the stem and leaf essential oils from Piper flaviflorum from Xishuangbanna, SW China. Nat. Prod. Commun. 2014, 9, 1011–1014. [Google Scholar] [CrossRef] [Green Version]
  58. Haddouchi, F.; Chaouche, T.M.; Zaouali, Y.; Ksouri, R.; Attou, A.; Benmansour, A. Chemical composition and antimicrobial activity of the essential oils from four Ruta species growing in Algeria. Food Chem. 2013, 141, 253–258. [Google Scholar] [CrossRef]
  59. Piras, A.; Cocco, V.; Falconieri, D.; Porcedda, S.; Marongiu, B.; Maxia, A.; Frau, M.A.; Gonçalves, M.J.; Cavaleiro, C.; Salgueiro, L. Isolation of the volatile oil from Satureja thymbra by supercritical carbon dioxide extraction: Chemical composition and biological activity. Nat. Prod. Commun. 2011, 6, 1523–1526. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  60. Li, R.; Yang, J.-J.; Song, X.-Z.; Wang, Y.-F.; Corlett, R.; Xu, Y.-K.; Hu, H.B. Chemical composition and the cytotoxic, antimicrobial, and anti-inflammatory activities of the fruit peel essential oil from Spondias pinnata (Anacardiaceae) in Xishuangbanna, southwest China. Molecules 2020, 25, 343. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  61. Pinto, E.; Gonçalves, M.J.; Hrimpeng, K.; Pinto, J.; Vaz, S.; Vale-Silva, L.A. Antifungal activity of the essential oil of Thymus villosus subsp. lusitanicus against Candida, Cryptococcus, Aspergillus and dermatophyte species. Ind Crops Prod. 2013, 51, 93–99. [Google Scholar] [CrossRef]
  62. Zapata, B.; Durán, C.; Stashenko, E.; Betancur-Galvis, L.; Mesa-Arango, A.C. Actividad antimicótica y citotóxica de aceites esenciales de plantas de la familia Asteraceae. Rev. Iberoam. Micol. 2010, 27, 101–103. [Google Scholar] [CrossRef] [PubMed]
  63. Puškárová, A.; Bučková, M.; Kraková, L.; Pangallo, D.; Kozics, K. The antibacterial and antifungal activity of six essential oils and their cyto/genotoxicity to human HEL 12469 cells. Sci. Rep. 2017, 7, 8211. [Google Scholar] [CrossRef] [Green Version]
  64. Aljaafari, M.N.; AlAli, A.O.; Baqais, L.; Alqubaisy, M.; AlAli, M.; Molouki, A.; Ong-Abdullah, J.; Abushelaibi, A.; Lai, K.S.; Lim, S.H. An overview of the potential therapeutic applications of essential oils. Molecules 2021, 26, 628. [Google Scholar] [CrossRef]
  65. Hlebová, M.; Hleba, L.; Medo, J.; Kováčik, A.; Čuboň, J.; Ivana, C.; Uzsáková, V.; Božik, M.; Klouček, P. Antifungal and synergistic activities of some selected essential oils on the growth of significant indoor fungi of the genus Aspergillus. J. Environ. Sci. Health Part A 2021, 56, 1335–1346. [Google Scholar] [CrossRef]
  66. Pekmezovic, M.; Aleksic, I.; Barac, A.; Arsic-Arsenijevic, V.; Vasiljevic, B.; Nikodinovic-Runic, J.; Senerovic, L. Prevention of polymicrobial biofilms composed of Pseudomonas aeruginosa and pathogenic fungi by essential oils from selected Citrus species. Pathog. Dis. 2016, 74, 102. [Google Scholar] [CrossRef] [Green Version]
  67. Kumamoto, C.A.; Vinces, M.D. Alternative Candida albicans lifestyles growth on surfaces. Annu. Rev. Microbiol. 2005, 59, 113–133. [Google Scholar] [CrossRef]
  68. Meena, D.S.; Kumar, D. Candida Pneumonia: An innocent bystander or a silent killer? Med. Princ. Pract. 2022, 31, 98–102. [Google Scholar] [CrossRef]
  69. Palmeira-de-Oliveira, A.; Salgueiro, L.; Palmeira-de-Oliveira, R.; Martinez-de-Oliveira, J.; Pina-Vaz, C.; Queiroz, J.; Queiroz, J.A.; Rodrigues, A.G. Anti-Candida activity of essential oils. Mini-Rev. Med. Chem. 2009, 9, 1292–1305. [Google Scholar] [CrossRef]
  70. Karpiński, T.M. Essential oils of Lamiaceae family plants as antifungals. Biomolecules 2020, 10, 103. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  71. Guimarães, R.; Milho, C.; Liberal, Â.; Silva, J.; Fonseca, C.; Barbosa, A.; Ferreira, I.C.; Alves, M.J.; Barros, L. Antibiofilm potential of medicinal plants against Candida spp. oral biofilms: A review. Antibiotics 2021, 10, 1142. [Google Scholar] [CrossRef] [PubMed]
  72. Karpiński, T.M.; Ożarowski, M.; Seremak-Mrozikiewicz, A.; Wolski, H.; Adamczak, A. Plant preparations and compounds with activities against biofilms formed by Candida spp. J. Fungi 2021, 7, 360. [Google Scholar] [CrossRef] [PubMed]
  73. Shala, A.; Singh, S.; Hameed, S.; Khurana, S.M.P. Essential oils as alternative promising anti-candidal agents: Progress and prospects. Curr. Pharm. Des. 2022, 28, 58–70. [Google Scholar] [CrossRef]
  74. Horton, M.V.; Johnson, C.J.; Kernien, J.F.; Patel, T.D.; Lam, B.C.; Cheong, J.Z.A.; Meudt, J.J.; Shanmuganayagam, D.; Kalan, L.R.; Nett, J.E. Candida auris forms high-burden biofilms in skin niche conditions and on porcine skin. mSphere 2020, 5, e00910-19. [Google Scholar] [CrossRef] [Green Version]
  75. Tran, H.N.H.; Graham, L.; Adukwu, E.C. In vitro antifungal activity of Cinnamomum zeylanicum bark and leaf essential oils against Candida albicans and Candida auris. Appl. Microbiol. Biotechnol. 2020, 104, 8911–8924. [Google Scholar] [CrossRef]
  76. Ferreira, O.O.; da Silva, S.H.M.; de Oliveira, M.S.; Andrade, E.H.d.A. Chemical composition and antifungal activity of Myrcia multiflora and Eugenia florida essential oils. Molecules 2021, 26, 7259. [Google Scholar] [CrossRef]
  77. Spengler, G.; Gajdács, M.; Donadu, M.G.; Usai, M.; Marchetti, M.; Ferrari, M.; Mazzarello, V.; Zanetti, S.; Nagy, F.; Kovács, R. Evaluation of the antimicrobial and antivirulent potential of essential oils isolated from Juniperus oxycedrus L. ssp. macrocarpa aerial parts. Microorganisms 2022, 10, 758. [Google Scholar] [CrossRef]
  78. de Alteriis, E.; Maione, A.; Falanga, A.; Bellavita, R.; Galdiero, S.; Albarano, L.; Salvatore, M.M.; Galdiero, E.; Guida, M. Activity of free and liposome-encapsulated essential oil from Lavandula angustifolia against persister-derived biofilm of Candida auris. Antibiotics 2021, 11, 26. [Google Scholar] [CrossRef]
  79. Baldim, I.; Paziani, M.H.; Grizante Barião, P.H.; Kress, M.R.v.Z.; Oliveira, W.P. Nanostructured lipid carriers loaded with Lippia sidoides essential oil as a strategy to combat the multidrug-resistant Candida auris. Pharmaceutics 2022, 14, 180. [Google Scholar] [CrossRef]
  80. McGregor, R.C.; Parker, K.A.; Hornby, J.M.; Latta, L.C. Microbial population dynamics under microdoses of the essential oil arborvitae. BMC Complement. Altern. Med. 2019, 19, 247. [Google Scholar] [CrossRef] [PubMed]
  81. Ribeiro, R.; Fernandes, L.; Costa, R.; Cavaleiro, C.; Salgueiro, L.; Henriques, M.; Rodrigues, M.E. Comparing the effect of Thymus spp. essential oils on Candida auris. Ind. Crops Prod. 2022, 178, 114667. [Google Scholar] [CrossRef]
  82. Shaban, S.; Patel, M.; Ahmad, A. Improved efficacy of antifungal drugs in combination with monoterpene phenols against Candida auris. Sci. Rep. 2020, 10, 1162. [Google Scholar] [CrossRef] [PubMed]
  83. Setianingrum, F.; Rautemaa-Richardson, R.; Denning, D.W. Pulmonary cryptococcosis: A review of pathobiology and clinical aspects. Med. Mycol. 2019, 57, 133–150. [Google Scholar] [CrossRef]
  84. Cavaleiro, C.; Salgueiro, L.; Gonçalves, M.-J.; Hrimpeng, K.; Pinto, J.; Pinto, E. Antifungal activity of the essential oil of Angelica major against Candida, Cryptococcus, Aspergillus and dermatophyte species. J. Nat. Med. 2015, 69, 241–248. [Google Scholar] [CrossRef]
  85. Li, Z.-J.; Njateng, G.S.S.; He, W.-J.; Zhang, H.-X.; Gu, J.-L.; Chen, S.-N.; Du, Z.Z. Chemical composition and antimicrobial activity of the essential oil from the edible aromatic plant Aristolochia delavayi. Chem. Biodivers. 2013, 10, 2032–2041. [Google Scholar] [CrossRef]
  86. Abu-Darwish, M.S.; Cabral, C.; Gonçalves, M.J.; Cavaleiro, C.; Cruz, M.T.; Efferth, T.; Salgueiro, L. Artemisia herba-alba essential oil from Buseirah (South Jordan): Chemical characterization and assessment of safe antifungal and anti-inflammatory doses. J. Ethnopharmacol. 2015, 174, 153–160. [Google Scholar] [CrossRef]
  87. Abu-Darwish, M.S.; Cabral, C.; Gonçalves, M.J.; Cavaleiro, C.; Cruz, M.T.; Zulfiqar, A.; Khan, I.A.; Efferth, T.; Salgueiro, L. Chemical composition and biological activities of Artemisia judaica essential oil from southern desert of Jordan. J. Ethnopharmacol. 2016, 191, 161–168. [Google Scholar] [CrossRef]
  88. Zuzarte, M.; Correia, P.M.P.; Alves-Silva, J.M.; Gonçalves, M.J.; Cavaleiro, C.; Cruz, T.; Salgueiro, L. Antifungal and anti-inflammatory potential of Bupleurum rigidum subsp. paniculatum (Brot.) H.Wolff essential oil. Antibiotics 2021, 10, 592. [Google Scholar] [CrossRef]
  89. Lee, J.-H. Comparison of chemical compositions and antimicrobial activities of essential oils from three conifer trees; Pinus densiflora, Cryptomeria japonica, and Chamaecyparis obtusa. J. Microbiol. Biotechnol. 2009, 19, 391–396. [Google Scholar] [CrossRef] [Green Version]
  90. van Vuuren, S.F.; Viljoen, A.M. In vitro evidence of phyto-synergy for plant part combinations of Croton gratissimus (Euphorbiaceae) used in African traditional healing. J. Ethnopharmacol. 2008, 119, 700–704. [Google Scholar] [CrossRef] [PubMed]
  91. Alves-Silva, J.M.; Zuzarte, M.; Gonçalves, M.J.; Cavaleiro, C.; Cruz, M.T.; Cardoso, S.M.; Salgueiro, L. New claims for wild carrot (Daucus carota subsp. carota) essential oil. Evid.-Based Complement. Altern. Med. 2016, 2016, 9045196. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  92. Tavares, A.C.; Gonçalves, M.J.; Cruz, M.T.; Cavaleiro, C.; Lopes, M.C.; Canhoto, J.; Salgueiro, L.R. Essential oils from Distichoselinum tenuifolium: Chemical composition, cytotoxicity, antifungal and anti-inflammatory properties. J. Ethnopharmacol. 2010, 130, 593–598. [Google Scholar] [CrossRef] [PubMed]
  93. Cabral, C.; Miranda, M.; Gonçalves, M.J.; Cavaleiro, C.; Cruz, M.T.; Salgueiro, L. Assessment of safe bioactive doses of Foeniculum vulgare Mill. essential oil from Portugal. Nat. Prod. Res. 2017, 31, 2654–2659. [Google Scholar] [CrossRef]
  94. Khoury, M.; El Beyrouthy, M.; Ouaini, N.; Eparvier, V.; Stien, D.; Hirtellina Lobelii, D.C. Essential oil, its constituents, its combination with antimicrobial drugs and its mode of action. Fitoterapia 2019, 133, 130–136. [Google Scholar] [CrossRef]
  95. Violante, I.M.P.; Garcez, W.S.; Barbosa, C.d.S.; Garcez, F.R. Chemical composition and biological activities of essential oil from Hyptis crenata growing in the Brazilian cerrado. Nat. Prod. Commun. 2012, 7, 1387–1389. [Google Scholar] [CrossRef] [Green Version]
  96. Mondello, F. In vitro and in vivo activity of tea tree oil against azole-susceptible and -resistant human pathogenic yeasts. J. Antimicrob. Chemother. 2003, 51, 1223–1229. [Google Scholar] [CrossRef]
  97. Tullio, V.; Roana, J.; Scalas, D.; Mandras, N. Evaluation of the antifungal activity of Mentha x piperita (Lamiaceae) of Pancalieri (Turin, Italy) essential oil and its synergistic interaction with azoles. Molecules 2019, 24, 3148. [Google Scholar] [CrossRef] [Green Version]
  98. Piras, A.; Porcedda, S.; Falconieri, D.; Maxia, A.; Gonçalves, M.; Cavaleiro, C.; Salgueiro, L. Antifungal activity of essential oil from Mentha spicata L. and Mentha pulegium L. growing wild in Sardinia Island (Italy). Nat. Prod. Res. 2021, 35, 993–999. [Google Scholar] [CrossRef]
  99. Omoruyi, B.; Afolayan, A.; Bradley, G. Chemical composition profiling and antifungal activity of the essential oil and plant extracts of Mesembryanthemum edule (L.) bolus leaves. Afr. J. Tradit. Complement Altern. Med. 2014, 11, 19. [Google Scholar] [CrossRef] [Green Version]
  100. Fabri, R.L.; Coimbra, E.S.; Almeida, A.C.; Siqueira, E.P.; Alves, T.M.A.; Zani, C.L.; Scio, E. Essential oil of Mitracarpus frigidus as a potent source of bioactive compounds. An. Acad. Bras. Cienc. 2012, 84, 1073–1080. [Google Scholar] [CrossRef] [PubMed]
  101. Bouzabata, A.; Bazzali, O.; Cabral, C.; Gonçalves, M.J.; Cruz, M.T.; Bighelli, A.; Tomi, F. New compounds, chemical composition, antifungal activity and cytotoxicity of the essential oil from Myrtus nivellei Batt. & Trab., an endemic species of Central Sahara. J. Ethnopharmacol. 2013, 149, 613–620. [Google Scholar] [CrossRef] [PubMed]
  102. Valente, J.; Zuzarte, M.; Gonçalves, M.J.; Lopes, M.C.; Cavaleiro, C.; Salgueiro, L.; Cruz, M.T. Antifungal, antioxidant and anti-inflammatory activities of Oenanthe crocata L. essential oil. Food Chem. Toxicol. 2013, 62, 349–354. [Google Scholar] [CrossRef] [PubMed]
  103. Marengo, A.; Piras, A.; Falconieri, D.; Porcedda, S.; Caboni, P.; Cortis, P.; Maxia, A. Chemical and biomolecular analyses to discriminate three taxa of Pistacia genus from Sardinia Island (Italy) and their antifungal activity. Nat. Prod. Res. 2018, 32, 2766–2774. [Google Scholar] [CrossRef] [PubMed]
  104. Piras, A.; Marzouki, H.; Maxia, A.; Marengo, A.; Porcedda, S.; Falconieri, D.; Gonçalves, M.J.; Cavaleiro, C.; Salgueiro, L. Chemical characterisation and biological activity of leaf essential oils obtained from Pistacia terebinthus growing wild in Tunisia and Sardinia Island. Nat. Prod. Res. 2017, 31, 2684–2689. [Google Scholar] [CrossRef]
  105. Satyal, P.; Powers, C.; Parducci, V.R.; McFeeters, R.; Setzer, W. Chemical composition, enantiomeric distribution, and antifungal activity of the oleoresin essential oil of Protium amazonicum from Ecuador. Medicines 2017, 4, 70. [Google Scholar] [CrossRef] [Green Version]
  106. Martins, A.; Salgueiro, L.; Gonçalves, M.; Proença da Cunha, A.; Vila, R.; Cañigueral, S. Essential oil composition and antimicrobial activity of Santiria trimera Bark. Planta Med. 2003, 69, 77–79. [Google Scholar] [CrossRef]
  107. Alves-Silva, J.M.; Zuzarte, M.; Gonçalves, M.J.; Cruz, M.T.; Cavaleiro, C.; Salgueiro, L. Unveiling the bioactive potential of the essential oil of a Portuguese endemism, Santolina impressa. J. Ethnopharmacol. 2019, 244, 112120. [Google Scholar] [CrossRef]
  108. Alves-Silva, J.M.; Piras, A.; Porcedda, S.; Falconieri, D.; Maxia, A.; Gonçalves, M.J.; Cruz, M.T.; Salgueiro, L. Chemical characterization and bioactivity of the essential oil from Santolina insularis, a Sardinian endemism. Nat. Prod. Res. 2022, 36, 445–449. [Google Scholar] [CrossRef]
  109. Marongiu, B.; Piras, A.; Porcedda, S.; Falconieri, D.; Frau, M.A.; Maxia, A.; Gonçalves, M.J.; Cavaleiro, C.; Salgueiro, L. Antifungal activity and chemical composition of essential oils from Smyrnium olusatrum L. (Apiaceae) from Italy and Portugal. Nat. Prod. Res. 2012, 26, 993–1003. [Google Scholar] [CrossRef]
  110. Piras, A.; Falconieri, D.; Bagdonaite, E.; Maxia, A.; Gonçalves, M.J.; Cavaleiro, C.; Salgueiro, L.; Porcedda, S. Chemical composition and antifungal activity of supercritical extract and essential oil of Tanacetum vulgare growing wild in Lithuania. Nat. Prod. Res. 2014, 28, 1906–1909. [Google Scholar] [CrossRef] [PubMed]
  111. Piras, A.; Maccioni, A.; Falconieri, D.; Porcedda, S.; Gonçalves, M.J.; Alves-Silva, J.M.; Silva, A.; Cruz, M.T.; Salgueiro, L.; Maxia, A. Chemical composition and biological activity of essential oil of Teucrium scordium L. subsp. scordioides (Schreb.) Arcang. (Lamiaceae) from Sardinia Island (Italy). Nat. Prod. Res. 2021, 1–8. [Google Scholar] [CrossRef] [PubMed]
  112. Pinto, E.; Gonçalves, M.-J.; Cavaleiro, C.; Salgueiro, L. Antifungal activity of Thapsia villosa essential oil against Candida, Cryptococcus, Malassezia, Aspergillus and dermatophyte species. Molecules 2017, 22, 1595. [Google Scholar] [CrossRef] [Green Version]
  113. Alves, M.; Gonçalves, M.J.; Zuzarte, M.; Alves-Silva, J.M.; Cavaleiro, C.; Cruz, M.T.; Salgueiro, L. Unveiling the antifungal potential of two Iberian Thyme essential oils: Effect on C. albicans germ tube and preformed biofilms. Front. Pharm. 2019, 10, 446. [Google Scholar] [CrossRef]
  114. Cabral, C.; Gonçalves, M.J.; Cavaleiro, C.; Sales, F.; Boyom, F.; Salgueiro, L. Composition and anti-fungal activity of the essential oil from Cameroonian Vitex rivularis Gürke. Nat. Prod. Res. 2009, 23, 1478–1484. [Google Scholar] [CrossRef]
  115. Abu-Darwish, M.S.; Cabral, C.; Gonçalves, M.J.; Cavaleiro, C.; Cruz, M.T.; Paoli MTomi, F.; Efferth, T.; Salgueiro, L. Ziziphora tenuior, L. essential oil from Dana Biosphere Reserve (Southern Jordan); Chemical characterization and assessment of biological activities. J. Ethnopharmacol. 2016, 194, 963–970. [Google Scholar] [CrossRef]
  116. Powers, C.N.; Satyal, P.; Mayo, J.A.; McFeeters, H.; McFeeters, R.L. Bigger data approach to analysis of essential oils and their antifungal activity against Aspergillus niger, Candida albicans, and Cryptococcus neoformans. Molecules 2019, 24, 2868. [Google Scholar] [CrossRef] [Green Version]
  117. Powers, C.; Osier, J.; McFeeters, R.; Brazell, C.; Olsen, E.; Moriarity DSatyal, P.; Setzer, W.N. Antifungal and cytotoxic activities of sixty commercially-available essential oils. Molecules 2018, 23, 1549. [Google Scholar] [CrossRef] [Green Version]
  118. Lawson, S.K.; Sharp, L.G.; Powers, C.N.; McFeeters, R.L.; Satyal, P.; Setzer, W.N. Volatile compositions and antifungal activities of native American medicinal plants: Focus on the Asteraceae. Plants 2020, 9, 126. [Google Scholar] [CrossRef] [Green Version]
  119. Scalas, D.; Mandras, N.; Roana, J.; Tardugno, R.; Cuffini, A.M.; Ghisetti, V.; Benvenuti, S.; Tullio, V. Use of Pinus sylvestris L. (Pinaceae), Origanum vulgare L. (Lamiaceae), and Thymus vulgaris L. (Lamiaceae) essential oils and their main components to enhance itraconazole activity against azole susceptible/not-susceptible Cryptococcus neoformans strains. BMC Complement Altern. Med. 2018, 18, 143. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  120. Cardoso, N.N.R.; Alviano, C.S.; Blank, A.F.; Romanos, M.T.V.; Fonseca, B.B.; Rozental, S.; Rodrigues, I.A.; Alviano, D.S. Synergism effect of the essential oil from Ocimum basilicum var. Maria Bonita and its major components with fluconazole and its influence on ergosterol biosynthesis. Evid.-Based Complement. Altern. Med. 2016, 2016, 5647182. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  121. de Rapper, S.; Van Vuuren, S.F.; Kamatou, G.P.P.; Viljoen, A.M.; Dagne, E. The additive and synergistic antimicrobial effects of select frankincense and myrrh oils—A combination from the pharaonic pharmacopoeia. Lett. Appl. Microbiol. 2012, 54, 352–358. [Google Scholar] [CrossRef] [PubMed]
  122. Kumari, P.; Mishra, R.; Arora, N.; Chatrath, A.; Gangwar, R.; Roy, P.; Prasad, R. Antifungal and anti-biofilm activity of essential oil active components against Cryptococcus neoformans and Cryptococcus laurentii. Front. Microbiol. 2017, 8, 2161. [Google Scholar] [CrossRef]
  123. Mouton, J.W.; Meletiadis, J.; Voss, A.; Turnidge, J. Variation of MIC measurements: The contribution of strain and laboratory variability to measurement precision. J. Antimicrob. Chemother. 2018, 73, 2374–2379. [Google Scholar] [CrossRef] [Green Version]
  124. de Lira Mota, K.; de Oliveira Pereira, F.; de Oliveira, W.; Lima, I.; de Oliveira Lima, E. Antifungal activity of Thymus vulgaris L. essential oil and its constituent phytochemicals against Rhizopus oryzae: Interaction with ergosterol. Molecules 2012, 17, 14418–14433. [Google Scholar] [CrossRef] [Green Version]
  125. do Prado, A.C.; Garces, H.G.; Bagagli, E.; Rall, V.L.M.; Furlanetto, A.; Junior, A.F.; Furtado, F.B. Schinus molle essential oil as a potential source of bioactive compounds: Antifungal and antibacterial properties. J. Appl. Microbiol. 2019, 126, 516–522. [Google Scholar] [CrossRef]
  126. Waller, S.B.; Madrid, I.M.; Ferraz, V.; Picoli, T.; Cleff, M.B.; de Faria, R.O.; Meireles, M.C.; de Mello, J.R. Cytotoxicity and anti-Sporothrix brasiliensis activity of the Origanum majorana Linn. oil. Braz. J. Microbiol. 2016, 47, 896–901. [Google Scholar] [CrossRef] [Green Version]
  127. Brilhante, R.S.N.; de Lima, R.A.C.; Caetano, E.P.; Leite, J.J.G.; Castelo-Branco D de, S.C.M.; Ribeiro, J.F.; Bandeira, T.D.; Cordeiro, R.D.; Monteiro, A.J.; Sidrim,, J.C.C.; et al. Effect of farnesol on growth, ergosterol biosynthesis, and cell permeability in Coccidioides posadasii. Antimicrob. Agents Chemother. 2013, 57, 2167–2170. [Google Scholar] [CrossRef] [Green Version]
  128. Brilhante, R.S.N.; de Lima, R.A.C.; Marques, F.J.d.F.; Silva, N.F.; Caetano, É.P.; Castelo, D.D.; Bandeira, T.D.; Moreira, J.L.; de Aguiar Cordeiro, R.; Monteiro, A.J.; et al. Histoplasma capsulatum in planktonic and biofilm forms: In vitro susceptibility to amphotericin B, itraconazole and farnesol. J. Med. Microbiol. 2015, 64, 394–399. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  129. Brilhante, R.S.; Silva, N.F.; Marques, F.J.; Castelo-Branco, D.D.; Lima, R.A.; Malaquias, A.D.; Caetano, E.P.; Barbosa, G.R.; Camargo, Z.P.; Rodrigues, A.M.; et al. In vitro inhibitory activity of terpenic derivatives against clinical and environmental strains of the Sporothrix schenkii complex. Med. Mycol. 2015, 53, 93–98. [Google Scholar] [CrossRef] [Green Version]
  130. Brilhante, R.S.; Pereira, V.S.; Oliveira, J.S.; Rodrigues, A.M.; de Camargo, Z.P.; Pereira-Neto, W.A.; Nascimento, N.R.; Castelo-Branco, D.S.; Cordeiro, R.A.; Sidrim, J.J.; et al. Terpinen-4-ol inhibits the growth of Sporothrix schenckii complex and exhibits synergism with antifungal agents. Future Microbiol. 2019, 14, 1221–1233. [Google Scholar] [CrossRef] [PubMed]
  131. Brilhante, R.S.; Caetano, É.P.; Lima, R.A.; Marques, F.J.; Castelo-Branco, D.D.; Melo, C.V.; Guedes, G.M.; Oliveira, J.S.; Camargo, Z.P.; Moreira, J.L.; et al. Terpinen-4-ol, tyrosol, and β-lapachone as potential antifungals against dimorphic fungi. Braz. J. Microbiol. 2016, 47, 917–924. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  132. Lee, S.H.; Lee, J.R.; Lunde, C.S.; Kubo, I. In vitro antifungal susceptibilities of Candida albicans and other fungal pathogens to polygodial, a sesquiterpene dialdehyde. Planta Med. 1999, 65, 204–208. [Google Scholar] [CrossRef]
  133. Mani-López, E.; Cortés-Zavaleta, O.; López-Malo, A. A review of the methods used to determine the target site or the mechanism of action of essential oils and their components against fungi. SN Appl. Sci. 2021, 3, 44. [Google Scholar] [CrossRef]
  134. Costa-Orlandi, C.; Sardi, J.; Pitangui, N.; de Oliveira, H.; Scorzoni, L.; Galeane, M.C.; Medina-Alarcón, K.P.; Melo, W.C.; Marcelino, M.Y.; Braz, J.D.; et al. Fungal biofilms and polymicrobial diseases. J. Fungi 2017, 3, 22. [Google Scholar] [CrossRef]
  135. Alves, J.C.O.; Ferreira, G.F.; Santos, J.R.; Silva, L.C.N.; Rodrigues, J.F.S.; Neto, W.R.; Farah, E.I.; Santos, Á.R.; Mendes, B.S.; Sousa, L.V.; et al. Eugenol induces phenotypic alterations and increases the oxidative burst in Cryptococcus. Front. Microbiol. 2017, 8, 2419. [Google Scholar] [CrossRef]
  136. Rajput, S.B.; Karuppayil, S.M. Small molecules inhibit growth, viability and ergosterol biosynthesis in Candida albicans. SpringerPlus 2013, 2, 26. [Google Scholar] [CrossRef] [Green Version]
  137. Pappas, P.G. Antifungal clinical trials and guidelines: What we know and do not know. Cold Spring Harb. Perspect. Med. 2014, 4, a019745. [Google Scholar] [CrossRef] [Green Version]
  138. Cimino, C.; Maurel, O.M.; Musumeci, T.; Bonaccorso, A.; Drago, F.; Souto, E.M.; Pignatello, R.; Carbone, C. Essential oils: Pharmaceutical applications and encapsulation strategies into lipid-based delivery systems. Pharmaceutics 2021, 13, 327. [Google Scholar] [CrossRef]
  139. Kamyar, M. Essential oil diffusion. Patent US20090169487 A1, 2 July 2009. [Google Scholar]
  140. Horváth, G.; Ács, K. Essential oils in the treatment of respiratory tract diseases highlighting their role in bacterial infections and their anti-inflammatory action: A review. Flavour Fragr. J. 2015, 30, 331–341. [Google Scholar] [CrossRef] [PubMed]
Table
Table 1. Causal agents of respiratory mycosis.
Table 1. Causal agents of respiratory mycosis.
FungiDiseaseSource of InfectionPathological ManifestationsDiagnosisAntifungals
Endemic
Blastomyces dermatitidisBlastomycosisSoilMild flu-like symptoms; chronic cutaneous disease with subcutaneous lesions on the face and handsMicroscopic observation of sputum samples; urine antigen test; enzyme immunoassayAmphotericin B, ketoconazole
Coccidioides immitisCoccidioidomycosis
(valley fever)		SoilGranulomatous lesions on the face and nose; meningitis in severe casesSerological testsAmphotericin B
Histoplasma capsulatumHistoplasmosisSoils with bird or bat droppingsFever, headache, and weakness with some chest discomfortChest X-ray; cultures grown on fungal selective media; direct fluorescence antibody and Giemsa stainingAmphotericin B, ketoconazole, itraconazole
Paracoccidioides sp.ParacoccidioidomycosisSoil near armadillo burrowsAdults: affects lungs and causes lesions in the mouth and throat;
Children: swollen lymph nodes and skin lesions		Chest X-ray, biopsy for fungal culture or to be examined under the microscope and blood testsItraconazole and amphotericin B; trimethoprim/sulfamethoxazole
Talaromyces marneffei (formerly Penicillium marneffei)Talaromycosis
(formerly Penicilliosis)		Plants and farmed animalsFever, weight loss, hepatosplenomegaly, lymphadenopathy, skin lesionsMicroscopy, histology, and cultureAmphotericin B or voriconazole followed by itraconazole
Sporothrix schenckiiSporotrichosis
(rose gardener’s disease)		Soil, Sphagnum moss, rose bushes and hayCutaneous nodules that spread and break down into abscesses and ulcers, with rare pulmonary involvementCultureItraconazole, amphotericin B
Opportunistic
Aspergillus fumigatusAspergillosisSoils and organic debrisAsthma-like allergic reactions; shortness of breath, wheezing, coughing, runny nose and headachesChest X-ray; microscopic examination of tissue and respiratory fluid samplesItraconazole, voriconazole
Candida spp.CandidiasisSkin and inside the bodyLocalized or diffuse pneumonia, nodular lesions, abscesses, and empyemaIsolation of the organism from lung tissue samplesFluconazole (milder cases), amphotericin B deoxycholate, lipid formulations
Cryptococcus neoformansCryptococcosisSoil, pigeon guano and tropical and subtropical treesFever, fatigue, and a dry cough; when spreading to the brain causes meningitis (headaches, sensitivity to light, and confusion)Microscopic examination of lung tissues or cerebrospinal fluidsAmphotericin B combined with flucytosine followed by fluconazole for up to 6 months
Nonpigmented fungi (other than Aspergillus and Penicillium or Zygomycetes) *HyalohyphomycosisSoil, water or on decomposing organic debrisLesions from local cutaneous, subcutaneous, corneal, or nasal mucosal disease to disseminated disease involving multiple organsCulture isolation and/or PCR Surgical removal with or without azole antifungal therapy
Rhizopus spp. and Mucor spp.Mucormycosis
(formerly zygomycosis)		Throughout the environmentFever, cough, chest pain, and shortness of breathTissue biopsy specimensAmphotericin B and surgical debridement removal in superficial infections
Dark melanin-pigmented dematiaceous fungi **PhaeohyphomycosisSoilSinusitis, subcutaneous nodules or abscesses, keratitis, lung masses, osteomyelitis, mycotic arthritis, endocarditis, brain abscess, and disseminated infectionExamination using Masson-Fontana staining; culture to identify causative speciesSurgery and/or itraconazole
Pneumocystis jiroveciiPneumocystis pneumonia (PCP)Person to person through the airFever, cough, and shortness of breathMicroscopic examination of tissue and fluid samples from the lungsTrimethoprim-sulfamethoxazole combination
Includes: * Acremonium, Fusarium, Geotrichum, Paecilomyces, Pseudallescheria, Sagenomella, Phialosimplex, Geosmithia, Geomyces, and Scedosporium; ** Bipolaris, Cladophialophora, Cladosporium, Exophiala, Fonsecaea, Phialophora, Ochronosis, Rhinocladiella, and Wangiella.
Table
Table 2. Antifungal effects of essential oils against Aspergillus fumigatus.
Table 2. Antifungal effects of essential oils against Aspergillus fumigatus.
Essential Oil
(Family)		Plant Part UsedMain CompoundsAntifungal EffectRef
Achillea millefolium
(Asteraceae)		flowering aerial partsSample A: α-asarone (33.3%),
α-pinene (17.2%),
β-bisabolene (16.6%);
Sample B: trans-thujone (29.0%),
trans-crhysanthenyl acetate (15.8%),
β-pinene (11.1%)		Broth macrodilution method:
MIC = 1.25 µL/mL and
MLC > 20 µL/mL (A);
MIC = 2.5–5 µL/mL and
MLC > 20 µL/mL (B)		[33]
Acorus calamus
(Acoraceae)		not identifiedβ-asarone (80.6%)Tube-dilution method:
MFC = 0.104 ± 0.016 mg/mL		[34]
Allium hookeri
(Amaryllidaceae)		rhizomesdi-2-propenyl trisulfide (31.8%),
diallyl disulfide (28.4%)		Broth macrodilution method:
MIC = 32 µg/mL and
MFC = 64 µg/mL		[35]
Apium graveolens
(Apiaceae)		flowering aerial partsSample A: neophytadiene (34.6%),
phytol isomer (11.8%);
Sample B: neophytadiene (45.2%),
limonene (24.0%)		Broth macrodilution method:
MIC = 0.16–0.32 µL/mL and MLC > 125 µL/mL (A);
MIC = 0.64 µL/mL and MLC > 20 µL/mL (B)		[36]
Artemisia absinthium
(Asteraceae)		leavesborneol (18.7%),
methyl hinokiate (11.9%) 		Tube-dilution method:
MIC = 91  ±  13 µg/mL		[37]
Artemisia persica
(Asteraceae)		aerial partslaciniata furanone E (17.1%),
artedouglasia oxide C (13.2%),
trans-pinocarveol (10.2%)		Broth macrodilution method:
MIC = 2.5 µL/mL and MFC = 10 µL/mL		[38]
Beilschmiedia madang
(Lauraceae)		barkδ-cadinene (20.5%),
α-cubebene (15.6%),
α-cadinol (10.6%)		Microdilution method:
MIC = 62.5 µg/mL		[39]
leafδ-cadinene (17.0%),
β-caryophyllene (10.3%),
α-cubebene (11.3%)		Microdilution method:
MIC = 250 µg/mL
Carum copticum
(Apiaceae)		not identifiedp-cymene (33.7%),
thymol (22.8%),
γ-terpinene (21.6%)		Broth macrodilution method:
MIC = 144 µg/mL		[40]
Centaurea solstitialis
(Asteraceae)		aerial partsgermacrene D (15.3%),
hexadecanoic acid (26.1%),
α-linolenic acid (17.9%)		Microdilution assay:
MIC = 1.9 µg/mL		[41]
Cinnamomum camphora
(Lauraceae)		leaf, branch, wood, root, leaf/branch, leaf/branch/woodleaf: camphor (93.1%);
branch: camphor (53.6%);
wood: camphor (53.2%) and 1,8-cineole (19.9%);
root: safrole (57.6%) and 1.8-cineole (18.1%);
leaf/branch: camphor (53.3%);
leaf/branch/wood: (59.5%)		Broth microdilution method:
MIC = 312.5 µg/mL (leaf, wood and root);
MIC = 156.3 µg/mL (branch and leaf/branch);
MIC = 78.1 µg/mL (leaf/branch/wood)		[42]
Cinnamomum glanduliferum (Lauraceae)barkeucalyptol (65.9%)Broth microdilution method:
MIC = 32.5 µg/mL		[43]
Cuminum cyminum
(Apiaceae)		aerial partsnot assessedBroth microdilution method:
MIC = 0.5 mg/mL
Broth macrodilution method:
MIC = 0.25 mg/mL		[44]
Daucus carota subsp. carota
(Apiaceae)		flowering and ripe umbelsflowering umbels:
α-pinene (37.9%),
geranyl acetate (15%);
ripe umbels—
Sample A: α-pinene (13.0%),
geranyl acetate (65.0%);
Sample B: β-bisabolene (51.0%),
(E)-methyl isoeugenol (10.0%)		Broth macrodilution method—Flowering umbels:
MIC = 2.5–5 µL/mL and
MLC > 20 µL/mL;
Ripe umbels:
MIC = 0.64–1.25 µL/mL and
MLC > 20 µL/mL (A);
MIC = 0.64 µL/mL and
MLC > 20 (B)		[45]
Gallesia integrifolia
(Phytolaccaceae)		fruit2,8-dithianonane (52.6%), dimethyl trisulfide (15.5%),
lenthionine (14.7%)		Modified microdilution method:
MFC = 0.02—0.18 mg/mL		[46]
Juniperus communis subsp. alpina
(Cupressaceae)		needlessabinene (26.2%),
α-pinene (12.9%),
limonene (10.4%)		Macrodilution broth method:
MIC = 2.5 µL/mL and
MFC = 10 µL/mL		[47]
Leptospermum petersonii
(Myrtaceae)		not identifiednot assessedBroth macrodilution method:
MIC and MFC = 0.05%		[48]
Lippia alba
(Verbenaceae)		stems and leavesCarvone chemotype:
carvone (25.3%),
limonene (22.4%),
geranial (10.4%);
Citral chemotype:
geranial (30.5%),
neral (23.6%)		Microdilution broth method:
MIC > 500 µg/mL (both chemotypes)		[49]
Lavandula luisieri
(Lamiaceae)		flowering aerial partsSample A: α-trans-necrodyl acetate (17.4%);
Sample B: 1,8-cineole (33.9%), fenchone (18.2%)		Broth macrodilution method:
MIC = 0.64 µL/mL and
MLC = 10–20 µL/mL (A);
MIC = 1.25 µL/mL and
MLC = 10 µL/mL (B)		[50]
Lavandula multifida
(Lamiaceae)		flowering aerial partscarvacrol (42.8%), cis-β-ocimene (27.4%);Broth macrodilution method:
MIC = 0.32 µL/mL and
MLC = 0.64 µL/mL		[51]
Lavandula pedunculata
(Lamiaceae)		aerial partsSample A: 1,8-cineole (34.3%);
Sample B: camphor (34.0%), 1,8-cineole (25.1%);
Sample C: fenchone (44.5%)		Broth macrodilution method:
MIC = 2.5 µL/mL and
MLC = 10 µL/mL (A);
MIC and MLC = 5 µL/mL (B);
MIC = 5 µL/mL and
MLC = 10 µL/mL (C)		[52]
Lavandula stoechas
(Lamiaceae)		aerial partsfenchone (37.0%),
camphor (27.3%)		Broth macrodilution method:
MIC = 1.25 µL/mL and
MLC ≥ 20µL/mL		[53]
Lavandula viridis
(Lamiaceae)		aerial parts1,8-cineole(34.5%),
camphor (13.4%),
α-pinene (9.0%),
linalool (7.9%) 		Broth macrodilution method:
MIC = 2.5 µL/mL and
MLC = 5–10 µL/mL		[54]
Melaleuca alternifolia
(Myrtaceae)		not identifiednot assessedBroth microdilution method:
MIC = 0.06–0.12%		[55]
Myrtus communis
(Myrtaceae)		leaves and flowersSample A: α-pinene (50.8%), linalool (14.8%), 1,8-cineole (13.3%);
Sample B: α-pinene (33.6%), linalool (14.8%), 1,8-cineole (13.3%) 		Broth macrodilution method:
MIC = 2.5 mg/mL and MLC >
10 mg/mL (both samples)		[56]
Nigella sativa
(Ranunculaceae)		aerial partsnot assessedBroth microdilution method:
MIC = 2 mg/mL
Broth macrodilution method:
MIC = 1.5 mg/mL		[44]
Piper flaviflorum
(Piperaceae)		leaf(E)-nerolidol (40.5%),
β-caryophyllene (14.6%)		Broth microdilution method:
MIC = 256 µg/mL and
MLC = 1024 µg/mL		[57]
Ruta angustifolia
(Rutaceae)		flowering aerial parts2-undecanone (82.5%),
2-decanone (10.0%)		Agar dilution method:
MIC < 3.5 µg/mL		[58]
Ruta chalepensis
(Rutaceae)		flowering aerial parts2-nonanone (32.8%),
2-undecanone (32.6%),
1-nonene (14.0%)		Agar dilution method:
MIC = 6.2–7.4 µg/mL
Ruta graveolens
(Rutaceae)		flowering aerial parts2-undecanone (55.4%),
nonanone (21.6%)		Agar dilution method:
MIC < 3.5 µg/mL
Ruta tuberculata
(Rutaceae)		flowering aerial partspiperitone (13.6%),
trans-p-menth-2-en-1-ol (13.1%),
cis-piperitol (12.3%),
cis-p-menth-2-en-1-ol (11.2%)		Agar dilution method:
MIC < 4.5 µg/mL
Satureja thymbra
(Lamiaceae)		aerial partsthymol (57.3%),
γ-terpinene (9.8%),
p-cymene (9.8%)		Broth macrodilution method:
MIC = 0.32 µL/mL and
MLC = 0.64 µL/mL		[59]
Spondias pinnata
(Anacardiaceae)		fruit peelsfurfural (17.1%),
α-terpineol (13.1%)		Broth microdilution method:
MIC = 16 µg/mL and
MFC = 32 µg/mL		[60]
Thymus villosus subsp. lusitanicus
(Lamiaceae)		aerial partsgeranyl acetate (25.0%),
terpinen-4-ol (13.5%) 		Broth macrodilution method:
MIC = 0.64–125 µL/mL and
MLC = 2.5–5.0 µL/mL		[61]
Thymus vulgaris
(Lamiaceae)		not identifiedthymol (44.7%),
γ-terpinene (26.0%),
α-cymene (21.2%)		Broth macrodilution method:
MIC = 144 µg/mL		[40]
Ziziphora clinopodioides
(Lamiaceae)		aerial partsnot assessedBroth microdilution method:
MIC = 1 mg/mL
Broth macrodilution method:
MIC = 0.5 mg/mL		[44]
MIC—Minimal Inhibitory Concentration; MBC—Minimal Bacterial Concentration; MFC—Minimal Fungicidal Concentration.
Table
Table 3. Antifungal effects of essential oils against Candida auris.
Table 3. Antifungal effects of essential oils against Candida auris.
Essential Oil
(Family)		Plant Part Used Main CompoundsAntifungal EffectMechanism of ActionRef
Cinnamomum zeylanicum
(Lauraceae)		barktrans-cinnamaldehyde (66.4%)Disc diffusion method
(diameter of inhibition):
77.37 ± 1.72 mm
Broth dilution method:
MIC < 0.03% and MFC < 0.03%		Modulation of cell
membrane permeability
(nuclei acid and protein release);
Hemolytic activity		[75]
leafeugenol (62.6%)Disc diffusion method
(diameter of inhibition):
35.40 ± 1.08 mm
Broth dilution method:
MIC = 0.06% and MFC = 0.25%
Eugenia florida
(Myrtaceae)		aerial partsseline-3,11-dien-6-α-ol (12.9%),
eremoligenol (11.0%),
γ-elemene (10.7%)		Disc diffusion method
(diameter of inhibition):
8 mm 		[76]
Juniperus oxycedrus subsp. macrocarpa
(Cupressaceae)		aerial partsα-pinene (56.6 ± 0.2%),
limonene (14.6 ± 0.11%),
β-pinene (13.4 ± 0.09%)		Planktonic MIC: 0.02%;
Sessile MIC: no biofilm formation		 [77]
Lavandula angustifolia
(Lamiaceae)		not identifiedlinalyl acetate (48.5%),
linalool (39.3%)		Growth reduction (0.01%)Modulation of biofilm related genes[78]
Lippia sidoides
(Verbenaceae)		leavesthymol (68.2%)Broth microdilution method:
Geometric mean MIC = 0.281 mg/mL		 [79]
Myrcia multiflora
(Myrtaceae)		aerial partsSample A: α-bulnesene (26.8%),
pogostol (21.3%);
Sample B: (E)-nerolidol (44.4%);
Sample C: (E)-nerolidol (92.2%)		Disc diffusion method
(diameter of inhibition):
9 mm (A), 10 mm (B) and 8 mm (C);
Broth dilution method:
MIC = 3.12 µL/mL (A) and 5 µL/mL (C); MFC > 12.5 µL/mL (A) and >50 µL/mL (C)
[Sample B not assessed]		 [76]
Thuja plicata
(Verbenaceae)		not identifiednot assessedInhibition of the intrinsic
rate of growth at 0.09% and 0.39%		 [80]
Thymus mastichina
(Lamiaceae)		flowering cupslinalool (31.9%),
α-terpineol (10.0%)		Disc diffusion method
(diameter of inhibition):
13.60 ± 1.36 mm 		Biofilm inhibition
(direct application and
vapor phase application)		[81]
Thymus satureioides
(Lamiaceae)		flowering cupsborneol (29.3%),
α-terpineol (15.9%)		Disc diffusion method
(diameter of inhibition):
20.00 ± 0.63 mm
Thymus vulgaris
(Lamiaceae)		flowering cupsthymol (63.1%),
1,8-cineole (10.0%)		Disc diffusion method
(diameter of inhibition):
42.33 ± 3.77 mm
Thymus zygis subsp. sylvestris
(Lamiaceae)		flowering aerial partsthymol (26.5%),
carvacrol (22.7%)		Disc diffusion method
(diameter of inhibition):
28.25 ± 1.0 mm
MIC—Minimal Inhibitory Concentration; MFC—Minimal Fungicidal Concentration.
Table
Table 4. Antifungal effects of essential oils against Cryptococcus neoformans.
Table 4. Antifungal effects of essential oils against Cryptococcus neoformans.
Essential Oil
(Family)		Plant Part UsedMain CompoundsAntifungal EffectRef
Achillea millefolium
(Asteraceae)		flowering aerial partsSample A:
α-asarone (33.3%),
β-bisabolene (16.6%) and
α-pinene (17.2%);
Sample B: trans-thujone (29.0%),
trans-crhysanthenyl acetate (15.8%)
and β-pinene (11.1%)		Broth macrodilution method:
MIC = 0.64 µL/mL and
MLC = 1.25 µL/mL (A);
MIC = 1.25 µL/mL and
MLC = 1.25 µL/mL (B)		[33]
Angelica major
(Apiaceae)		aerial partscis-β-ocimene (30.4 %),
α-pinene (21.8 %)		Broth macrodilution method:
MIC = 0.16 µL/mL and
MLC = 0.64 µL/mL		[84]
Apium graveolens
(Apiaceae)		flowering aerial partsSample A: neophytadiene (34.6%),
γ-himachalene (10.3%);
Sample B: neocnidilide (45.2%),
limonene (24.0%) 		Broth macrodilution method:
MIC and MLC = 0.16 µL/mL (A);
MIC = 0.32 µL/mL and MLC = 0.64 µL/mL (B)		[36]
Aristolochia delavayi
(Aristolochiaceae)		aerial parts(E)-dec-2-enal (52.0%)Broth microdilution method:
MIC = 7.81 µg/mL and
MFC = 62.5 µg/mL		[85]
Artemisia herba-alba
(Asteraceae)		aerial partsβ-thujone (25.1%),
α-thujone (22.9%),
1,8-cineole (20.1%),
camphor (10.5%)		Broth macrodilution method:
MIC = 0.64 mg/mL and
MLC = 0.64–125 mg/mL		[86]
Artemisia judaica
(Asteraceae)		aerial partspiperitone (30.4%),
camphor (16.1%),
ethyl cinnamate (11.0%)		Broth macrodilution method:
MIC = 0.16 µL/mL and
MLC = 0.64 µL/mL		[87]
Bupleurum rigidum subsp. paniculatum
(Apiaceae)		aerial partsα-pinene (36.0%),
β-pinene (26.1%),
limonene (10.5%) 		Broth macrodilution method:
MIC = 72 µg/mL and
MLC = 144 µg/mL		[88]
Chamaecyparis obtusa
(Cupressaceae)		needles and twigsbicyclo[2.2.1]heptan-2-ol (18.8%),
(+)-2-carene (17.4%),
sabinene (12.8%)		Broth microdilution method:
MIC > 2.18 mg/mL		[89]
Croton gratissimus
(Euphorbiaceae)		leavesnot assessedBroth microdilution method:
MIC = 4 mg/mL		[90]
Cryptomeria japonica
(Cupressaceae)		needles and twigskaur-16-ene (31.5%),
sabinene (11.1%),		Broth microdilution method: MIC > 2.18 mg/mL[89]
Daucus carota subsp. carota
(Apiaceae)		flowering and ripe umbelsFlowering umbels—Sample A:
α-pinene (37.9%), geranyl acetate (15.0%);
Sample B: carotol (25.1%),
β-bisabolene (17.6%);
Ripe umbels—Sample A:
α-pinene (13.0%),
geranyl acetate (65.0%);
Sample B: β-bisabolene (51.0%),
(E)-methyl isoeugenol (10.0%)		Broth macrodilution method—Flowering umbels:
MIC = 0.32–0.64 µL/mL
and MLC = 1.25–2.5 µL/mL (A);
MIC = 0.32 µL/mL and
MLC = 0.32–0.64 µL/mL (B);
Ripe umbels: MIC and MLC = 0.64 µL/mL (A);
MIC and MLC = 0.64–1.25µL/mL (B)		[45]
ripe umbels with seedsgeranyl acetate (29.0%),
α-pinene (27.2%)		Broth macrodilution method:
MIC and MLC = 0.16 µL/mL		[91]
Distichoselinum tenuifolium
(Apiaceae)		ripe umbels myrcene (84.6%)Broth macrodilution method:
MIC = 0.32–0.64 µL/mL
and MLC = 0.64 µL/mL		[92]
Foeniculum vulgare
(Apiaceae)		umbels and fruitsE-anetol (47.0%),
α-phellandrene (11.0%),
α-pinene (10.1%),
fenchone (10.8%)		Broth macrodilution method:
MIC = 0.32 µL/mL and
MLC = 0.64 µL/mL		[93]
Hirtellina lobelia
(Asteraceae)		aerial partsα-bisabolol (34.5%),
fokienol (12.0%)		Broth microdilution method:
MIC = 128 µL/mL		[94]
Hyptis crenata
(Lamiaceae)		aerial partsborneol (17.8%),
1,8-cineol (15.6%)		Broth microdilution method:
MIC = 62.5 µg/mL and
MFC = 125 µg/mL		[95]
Juniperus communis subsp. alpina
(Cupressaceae)		needlessabinene (26.2%),
α-pinene (12.9%)		Broth macrodilution method:
MIC = 1.25 µL/mL and
MFC = 1.25 µL/mL		[47]
Lavandula luisieri
(Lamiaceae)		flowering aerial partsSample A: α-trans-necrodyl acetate (17.4%);
Sample B: 1,8-cineole (33.9%),
fenchone (18.2%)		Broth macrodilution method:
MIC and MLC = 0.64 µL/mL (A);
MIC = 0.64 µL/mL and
MLC = 0.64–1.2 µL/mL (B)		[50]
Lavandula multifida
(Lamiaceae)		flowering aerial partscarvacrol (42.8%),
cis-β-ocimene (27.4%)		Broth macrodilution method:
MIC = 0.16 µL/mL and
MLC = 0.32 µL/mL		[51]
Lavandula pedunculata
(Lamiaceae)		aerial partsSample A: 1,8-cineole (34.3%);
Sample B: camphor (34%),
1,8-cineole (25.1%);
Sample C: fenchone (44.5%)		Broth macrodilution method:
MIC and MLC = 1.25 µL/mL (A);
MIC and MLC = 0.32–0.64 µL/mL (B);
MIC = 1.25 µL/mL and
MLC = 1.25–2.5µL/mL (C)		[52]
Lavandula viridis
(Lamiaceae)		aerial parts1,8-cineole(34.5%),
camphor (13.4%),
α-pinene (9.0%),
linalool (7.9%)		Broth macrodilution method:
MIC = 0.64 µL/mL and
MLC = 0.64 µL/mL		[54]
Melaleuca alternifolia
(Myrtaceae)		not identifiedterpinen-4-ol (42.4%),
γ-terpinene (20.7%)		Broth microdilution method:
MIC = 0.06–0.2%		[96]
Mentha x piperita
(Lamiaceae)		leavesmenthol (41.7%), menthone (21.8%)Broth microdilution method:
MIC = 0.06–0.125% and
MFC = 0.06–0.125%		[97]
Mentha pulegium
(Lamiaceae)		aerial partspulegone (86.2%)Broth macrodilution method:
MIC = 0.64 mg/mL and
MLC = 1.25 µL/mL		[98]
Mentha spicata
(Lamiaceae)		aerial partscarvone (62.9%)Broth macrodilution method:
MIC = 0.32 µL/mL and
MLC = 0.64–1.25 µL/mL
Mesembryanthemum edule(Aizoaceae)leavestetradecamethylcycloheptasiloxane (13.6%),
phytol (12.4%)		Broth microdilution method:
MIC = 0.08 mg/mL		[99]
Mitracarpus frigidus
(Rubiaceae)		aerial partslinalool (29.9%),
eugenol acetate (15.9%)		Broth microdilution method:
MIC = 8 µg/mL		[100]
Myrtus communis
(Myrtaceae)		dried leaves and flowersSample A: α-pinene (50.8%),
1,8-cineole (21.9%);
Sample B: α-pinene (33.6%),
linalool (14.8%), 1,8-cineole (13.3%) 		Broth macrodilution method:
MIC = 0.64 mg/mL and
MLC = 0.64–1.25 mg/mL (A);
MIC and MLC = 0.64 mg/mL (B)		[56]
Myrtus nivellei
(Myrtaceae)		aerial parts (10 samples)1,8-cineole (37.5%),
limonene (25.0%)		Broth macrodilution method:
MIC = 0.16 µL/mL and
MLC = 0.32 µL/mL		[101]
Oenanthe crocata
(Apiaceae)		aerial partstrans-β-ocimene (31.3%),
sabinene (29.0%),
cis-β-ocimene (12.3%)		Broth macrodilution method: MIC = 0.16 µL/mL and
MLC = 0.32 µL/mL		[102]
Pinus densiflora
(Pinaceae)		needles and twigsβ-phellandrene (16.7%),
(-)-α-pinene (14.9%),
1-β-pinene (10.5%),
α-fenchyl acetate (10.3%)		Broth microdilution method:
MIC = 0.545 mg/mL		[89]
Pistacia x saportae
(Anacardiaceae)		aerial partsα-pinene (30.3%),
(Z)-β-ocimene (26.7%),
(E)-β-ocimene (11.1%)		Broth macrodilution method:
MIC = 0.32 mg/mL and
MLC = 0.64–1.25 mg/mL		[103]
Pistacia lentiscus
(Anacardiaceae)		aerial partsterpinen-4-ol (25.2%),
α-phellandrene (11.9%),
β-phellandrene (10.2%),
γ-terpinene (10.1%)		Broth macrodilution method:
MIC = 0.32 mg/mL and MLC = 0.64 mg/mL
Pistacia terebinthus
(Anacardiaceae)		aerial partsterpinolene (35.2%),
α-pinene (35%) 		Broth macrodilution method:
MIC = 1.25 mg/mL and MLC = 2.5 mg/mL
leavesSample A: α-pinene (62.4%),
β-pinene (12.1%);
Sample B: terpinolene (35.2%), α-pinene (35.0%) 		Broth macrodilution method:
MIC = 0.32 µL/mL and
MLC = 0.64 µL/mL (A);
MIC = 1.25 µL/mL and
MLC = 2.5 µL/mL (B)		[104]
Protium amazonicum
(Myrtaceae)		oleoresinδ-3-carene (47.9%)Broth microdilution method:
MIC = 0 156 μg/mL		[105]
Santiria trimera
(Burseraceae)		barkα-pinene (66.6%),
β-pinene (20.0%)		Agar dilution method:
MIC < 0.71 μL/mL		[106]
Santolina impressa
(Asteraceae)		flowering aerial partsβ-pinene (22.5%),
1,8-cineole (10.0%)		Broth macrodilution method:
MIC = 0.27 mg/mL		[107]
Santolina insularis
(Asteraceae)		aerial partsβ-phellandrene (22.6%),
myrcene (11.4%)		Broth macrodilution method:
MIC = 0.13 mg/mL		[108]
Satureja thymbra
(Lamiaceae)		aerial partsthymol (57.3%),
γ-terpinene (9.8%),
β-caryophyllene,
p-cymene (9.8%)		Broth macrodilution method:
MIC = 0.16 µL/mL and
MLC = 0.32 µL/mL		[59]
Smyrnium olusatrum
(Apiaceae)		fruiting umbelsSample A: β-phellandrene (42.7%);
Sample B: acetoxyfurano-4(15)-eudesmene (17.6%)		Broth macrodilution method:
MIC = 0.32 µL/mL and
MLC = 0.64 µL/mL (A);
MIC and MLC = 0.64 µL/mL (B)		[109]
Tanacetum vulgare
(Asteraceae)		flowering aerial parts1,8-cineole (18.2%),
myrtenol (10.3%)		Broth macrodilution method:
MIC = 0.16 µL/mL and
MLC = 0.16–0.32 µL/mL		[110]
Teucrium scordium subsp. scordioides
(Lamiaceae)		aerial partsgermacrene D (25.1%),
δ-cadinene (12.9%),
alloaromadendrene (11.3%)		Broth macrodilution method:
MIC = 0.32 µL/mL and
MLC = 0.32 µL/mL		[111]
Thapsia villosa
(Apiaceae)		aerial partslimonene (57.5%),
methyleugenol (35.9%)		Broth macrodilution method:
MIC and MFC = 0.16 µL/mL		[112]
Thymus camphoratus
(Lamiaceae)		flowering aerial parts1,8-cineole (15.5%),
α-pinene (12.7%)		Broth macrodilution method:
MIC = 0.14 mg/mL and
MLC = 0.28 mg/mL (both oils)		[113]
Thymus carnosus
(Lamiaceae)		flowering aerial partsborneol (29.0%),
camphene (19.5%)
Thymus villosus subsp. lusitanicus
(Lamiaceae)		aerial partsterpinen-4-ol (13.5%),
geranyl acetate (25%)		Broth macrodilution method:
MIC = 0.16 µL/mL and
MLC = 0.16–0.32 µL/mL		[61]
Vitex rivularis
(Lamiaceae)		leaves and flowersSample A: germacrene D (12.6%);
Sample B: germacrene D (20.6%)		Broth macrodilution method:
MIC = 0.64–1.25 µL/mL and
MLC = 2.5–5 µL/mL (A);
MIC = 1.25 µL/mL and
MLC = 5–10 µL/mL (B)		[114]
Ziziphora tenuior
(Lamiaceae)		aerial partspulegone (46.8%),
p-menth-3-en-8-ol (12.5%)		Broth macrodilution method:
MIC = 0.16 µL/mL and
MLC = 0.64 µL/mL		[115]
MIC—Minimal Inhibitory Concentration; MFC—Minimal Fungicidal Concentration; MLC—Minimal Lethal Concentration.
Table
Table 5. In vitro antifungal effects of volatile compounds against respiratory fungi.
Table 5. In vitro antifungal effects of volatile compounds against respiratory fungi.
Fungal Strain TestedEssential Oil (Family)Plant Part UsedMainCompoundsAntifungal EffectRef
Rhizopus oryzaeThymus vulgaris
(Lamiaceae)		not identifiednot assessedDisc diffusion method
(diameter of inhibition): 32 mm;
Broth microdilution method:
MIC = 256–512 μg/mL;
MFC = 512–1024 μg/mL
(several strains tested)		[124]
Paracoccidioides brasiliensisSchinus molle
(Anacardiaceae)		leavesβ-pinene (25.2%),
epi-α-cadinol (21.3%),
α-pinene (18.7%),
myrcene (11.5%)		Broth microdilution method:
MIC and MLC = 39.06 μg/mL		[125]
Sporothrix schenckiiOriganum majorana
(Lamiaceae)		not identified1.8-cineole (20.9%),
terpeninen-4-ol (20.4%)		Broth microdilution method:
MIC and MLC ≤ 2.25 mg/mL		[126]
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Zuzarte, M.; Salgueiro, L. Essential Oils in Respiratory Mycosis: A Review. Molecules 2022, 27, 4140. https://doi.org/10.3390/molecules27134140

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Zuzarte M, Salgueiro L. Essential Oils in Respiratory Mycosis: A Review. Molecules. 2022; 27(13):4140. https://doi.org/10.3390/molecules27134140

Chicago/Turabian Style

Zuzarte, Mónica, and Lígia Salgueiro. 2022. "Essential Oils in Respiratory Mycosis: A Review" Molecules 27, no. 13: 4140. https://doi.org/10.3390/molecules27134140

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