molecules Review Antifungal Properties of Essential Oils and Their Compounds for Application in Skin Fungal Infections: Conventional and Nonconventional Approaches Aswir Abd Rashed 1,* , Devi-Nair Gunasegavan Rathi 1 , Nor Atikah Husna Ahmad Nasir 2 and Ahmad Zuhairi Abd Rahman 3,* 1 Nutrition, Metabolism and Cardiovascular Research Centre, Institute for Medical Research, National Institutes of Health, Ministry of Health Malaysia No.1, Jalan Setia Murni U13/52, Seksyen U13 Setia Alam, Shah Alam 40170, Malaysia; [email protected] 2 Department of Biology, Faculty of Applied Science, Universiti Teknologi MARA (Perlis Branch), Arau 02600, Malaysia; [email protected] 3 Cancer Research Centre, Institute for Medical Research, National Institutes of Health, Ministry of Health Malaysia, No.1, Jalan Setia Murni U13/52, Seksyen U13 Setia Alam, Shah Alam 40170, Malaysia * Correspondence: [email protected] (A.A.R.); [email protected] (A.Z.A.R.) Abstract: Essential oils (EOs) are known to have varying degrees of antimicrobial properties that are mainly due to the presence of bioactive compounds. These include antiviral, nematicidal, antifungal, insecticidal and antioxidant properties. This review highlights the potential of EOs Citation: Abd Rashed, A.; and their compounds for application as antifungal agents for the treatment of skin diseases via Rathi, D.-N.G.; Ahmad Nasir, N.A.H.; conventional and nonconventional approaches. A search was conducted using three databases Abd Rahman, A.Z. Antifungal Properties of Essential Oils and Their (Scopus, Web of Science, Google Scholar), and all relevant articles from the period of 2010–2020 Compounds for Application in Skin that are freely available in English were extracted. In our findings, EOs with a high percentage of Fungal Infections: Conventional and monoterpenes showed strong ability as potential antifungal agents. Lavandula sp., Salvia sp., Thymus Nonconventional Approaches. sp., Citrus sp., and Cymbopogon sp. were among the various species found to show excellent antifungal Molecules 2021, 26, 1093. properties against various skin diseases. Some researchers developed advanced formulations such as https://doi.org/10.3390/ gel, semi-solid, and ointment bases to further evaluate the effectiveness of EOs as antifungal agents. molecules26041093 To date, most studies on the application of EOs as antifungal agents were performed using in vitro techniques, and only a limited number pursued in vivo and intervention-based research. Academic Editors: Vivian Tullio, Alessandra Guerrini and Keywords: skin fungus; essential oils; in vitro; in vivo; intervention Domenico Cautela Received: 30 December 2020 Accepted: 31 January 2021 1. Introduction Published: 19 February 2021 Fungi are ubiquitous environmental microorganisms that may be categorized, accord- Publisher’s Note: MDPI stays neutral ing to their dimorphic morphology, as unicellular (yeast) or filamentous (molds). Almost with regard to jurisdictional claims in one million mycotic species have been reported to exist in nature, with approximately published maps and institutional affil- 200 species identified as human pathogenic [1]. It has been found in recent years that iations. fungal infections have contributed to increased mortality rates [2]. This phenomenon has been linked to certain age groups, especially premature neonates, infants and elderly people who are susceptible to underdeveloped or poor immune systems [3–5]. The most common species associated with deadly invasive and superficial infections are Candida sp., Copyright: © 2021 by the authors. Aspergillus sp., and Cryptococcus sp. [6]. In addition, Fusarium sp. has been shown to cause Licensee MDPI, Basel, Switzerland. opportunistic invasive fungal infections [5,7]. This article is an open access article Aspergillus spp. is a filamentous and ubiquitous fungi with A. fumigatus as the major distributed under the terms and species associated with human disease, followed by A. flavus, A. niger and A. terreus [3,8,9]. conditions of the Creative Commons In addition to the most common species, several other emerging species exist, including A. Attribution (CC BY) license (https:// clavatus, A. nidulans, A. glaucus and A. ustus [6,9]. Fusarium spp. are other fungi that can creativecommons.org/licenses/by/ cause human infections, and are the primary cause of fungal keratitis. This fungus is the 4.0/). Molecules 2021, 26, 1093. https://doi.org/10.3390/molecules26041093 https://www.mdpi.com/journal/molecules Molecules 2021, 26, x FOR PEER REVIEW 2 of 42 Molecules 2021, 26, 1093 2 of 44 cause human infections, and are the primary cause of fungal keratitis. This fungus is the secondsecond most most common common to to infect infect severely severely immunocompromised immunocompromised patients and cause dissem dissemi-‐ inatednated infection [[10].10]. F. solani has been identified identified as the most frequent pathogen in fusarial fusarial keratitiskeratitis incidence, while F.F. oxysporum oxysporumleads leads to to major major incidences incidences of of onychomycosis onychomycosis [11 [11––13]. 13].Candida Candidaspp. spp. are tiny,are tiny, oval-shaped oval‐shaped fungi fungi with with a thin a cell thin wall cell thatwall are that capable are capable of budding of bud or‐ dingfission. or fission. Among Among the identified the identified species, species, five are five the are leading the leading cause of cause invasive of invasive infections infec (C.‐ tionsalbicans, (C. C.albicans, glabrata, C. C. glabrata, parapsilosis, C. parapsilosis, C. tropicals C.and, tropicalsC. krusei and,)[14 C.]. krusei Invasive) [14]. candidiasis Invasive oftencan‐ didiasisoccurs as often a form occurs of healthcare-associated as a form of healthcare infection,‐associated where infection, affected where patients affected are typicallypatients arereceiving typically broad-spectrum receiving broad antibiotic‐spectrum treatment, antibiotic immunosuppressants,treatment, immunosuppressants, or suffering or from suf‐ feringcancer from [15]. cancer Candidiasis [15]. Candidiasis infections typically infections exist typically on the exist epithelial on the surfaces epithelial of surfaces the mouth, of thegastrointestinal mouth, gastrointestinal tract, vagina tract, and skin vagina surfaces. and skinC. albicans surfaces.remains C. albicans the most remains common the causemost commonof skin, nail cause and of mucous skin, nail membrane and mucous infections membrane in healthy infections individuals, in healthy in whom individuals, it may also in whominduce it more may severealso induce infections more of severe the vital infections organs of [16 the,17 ].vital organs [16,17]. InIn general, general, fungal fungal diseases areare differentiateddifferentiated into into four four groups: groups: dermatophytosis, dermatophytosis, subcu- sub‐ cutaneoustaneous mycoses, mycoses, systemic systemic mycoses mycoses and and other other mycoses mycoses [4]. [4]. Dermatophytosis Dermatophytosis is causedis caused by bydermatophytes dermatophytes that that attack attack and and grow grow on dead on dead animal animal keratin. keratin.Epidermophyton, Epidermophyton, Microsporum Micro‐ sporumand Trichophyton and Trichophytonare the are three the main three genera main genera related related to dermatophytes. to dermatophytes. Dermatophytes Dermato‐ phytesare known are known as a species as a species of fungi of fungi that typically that typically infect infect and invade and invade a living a living host’s host’s skin, skin, hair hairand and nails. nails. Diseases Diseases caused caused by by dermatophytes dermatophytes are are typically typically classified classified accordingaccording to the infectioninfection site, site, but but are are broadly broadly referred referred to toas tinea. as tinea. Several Several forms forms of tinea of tinea are common are common such assuch Tinea as capitisTinea capitis (scalp(scalp and hair), and hair),Tinea corporisTinea corporis (nonhairy(nonhairy skin), Tinea skin), barbaeTinea barbae(beard),(beard), Tinea crurisTinea cruris(groin),(groin), Tinea manuumTinea manuum (hand),(hand), Tinea pedisTinea (feet) pedis and(feet) Tinea and unguiumTinea unguium (nails, (nails,also called also onchomyosis)called onchomyosis) [18]. According [18]. According to current to currentpractice, practice, five classes five of classes conventional of conventional antifungal an- treatmentstifungal treatments are commonly are commonly applied. applied.Figure 1 Figureshows1 each shows antifungal each antifungal agent and agent its mecha and its‐ nismmechanism of action. of action. Figure 1. Conventional antifungal agents and their mechanisms of action (Adapted from [19]). Figure 1. Conventional antifungal agents and their mechanisms of action (Adapted from [19]). However,However, the the treatment treatment of of fungal infections has has encountered serious serious difficulties difficulties in thethe form form of of increased increased resistance resistance due due to to the the extensive extensive use use of of antifungal antifungal agents. agents. This This situa sit-‐ tionuation has has led led to the to the insight insight that that alternative, alternative, nonconventional nonconventional approaches approaches are arerequired required for effectivefor effective antifungal antifungal treatment treatment strategies. strategies. One Oneof the of possible the possible directions directions proposed proposed is the is usethe of use essential of essential oils (EOs) oils (EOs) as potential as potential antifungal