pharmaceuticals Review A Decade of Antifungal Leads from Natural Products: 2010–2019 Mohammed Aldholmi 1,2 , Pascal Marchand 3 , Isabelle Ourliac-Garnier 3 , Patrice Le Pape 3 and A. Ganesan 2,* 1 Department of Natural Products and Alternative Medicine, College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, Dammam 31441, Saudi Arabia; [email protected] 2 School of Pharmacy, University of East Anglia, Norwich Research Park, Norwich NR4 7TJ, UK 3 Université de Nantes, Cibles et Médicaments des Infections et du Cancer, IICiMed, EA 1155, F-44000 Nantes, France; [email protected] (P.M.); [email protected] (I.O.-G.); [email protected] (P.L.P.) * Correspondence: [email protected] Received: 29 November 2019; Accepted: 10 December 2019; Published: 12 December 2019 Abstract: In this review, we discuss novel natural products discovered within the last decade that are reported to have antifungal activity against pathogenic species. Nearly a hundred natural products were identified that originate from bacteria, algae, fungi, sponges, and plants. Fungi were the most prolific source of antifungal compounds discovered during the period of review. The structural diversity of these antifungal leads encompasses all the major classes of natural products including polyketides, shikimate metabolites, terpenoids, alkaloids, and peptides. Keywords: fungal pathogens; antifungal agents; natural products 1. Introduction The global increase in antimicrobial resistance among pathogenic bacteria, viruses, fungi, and parasites is a serious concern for human healthcare. In the case of fungi, more than one billion individuals worldwide are affected by fungal infections and the associated mortality, over 1.5 million deaths each year, is equivalent to that caused by tuberculosis and more than triple that of malaria [1]. Although relatively rare in healthy individuals, the incidence of superficial and invasive fungal infections has dramatically risen in recent years. This is due to a growing ‘at-risk’ population with impairments in their immune system, breaches in physical barriers to fungal entry, or an altered microbiome. Skin mycoses are predominantly caused by Trichophyton, Microsporum, and Epidermophyton genera while Candida, Cryptococcus, Aspergillus, and Pneumocystis genera, and Mucorales are the most common invasive fungal pathogens [2]. Meanwhile, emerging pathogenic fungi that are either new species such as the recently described Candida auris [3] or well-known species spreading in their ecological distribution represent additional threats to human health. The growing challenges posed by fungal diseases are further heightened as antifungal treatment is mainly limited to the azoles and echinocandins. The azoles are the most widely used antifungals and are synthetic compounds that reversibly inhibit cytochrome P450-dependent lanosterol or eburicol 14α-demethylase with moderate specificity for the fungal enzyme over the human counterpart [4]. Nevertheless, they suffer from off-target toxicity as well as issues with fungistatic rather than fungicidal activity in yeasts that promote the development of resistance. The major resistance mechanisms to azoles involve genetic mutations or increased expression of the target enzyme, or amplification or induction of efflux pumps. The echinocandins are fungal lipopeptide natural products (Figure1) that are non-competitive inhibitors of 1,3-β-glucan synthase, an enzyme involved in fungal cell Pharmaceuticals 2019, 12, 182; doi:10.3390/ph12040182 www.mdpi.com/journal/pharmaceuticals Pharmaceuticals 2019, 12, 182 2 of 21 Pharmaceuticals 2019, 12, x FOR PEER REVIEW 2 of 21 wall biosynthesis. While the natural products are not optimal in terms of pharmacokinetics, three semisyntheticpharmacokinetic derivativess, three aresemisynthetic approved for derivatives clinical use: are anidulafungin approved for prepared clinical from use: echinocandin anidulafungin B, caspofunginprepared from prepared echinocandin from pneumocandin B, caspofungin Bo, and prepared micafungin from prepared pneumocandin from FR901379 Bo, and [5 ].micafungin Although theprepared selectivity from of FR901379 the echinocandin [5]. Although target forthe fungiselectivity provides of the a good echinocandin safety profile, target these for fungi compounds provides are a largegood peptides, safety profile, requiring these intravenous compounds administration, are large peptides while, requiring mutations intravenous at hotspots administration in the target enzyme, while leadmutations to resistance. at hotspots In addition in the to thetarget azoles enzyme and echinocandins, lead to resistance the polyenes. In addition and pyrimidines to the azoles are twoand otherechinocandins, classes approved the polyenes for antifungal and pyrimidines therapy. The are naturaltwo other product classes polyenes approved (Figure for antifungal2) are macrolides therapy. isolatedThe natural from product various Streptomycespolyenes (Figurestrains. 2) Theare prototypicalmacrolides isolated amphotericin from Bvarious has been Streptomyces in clinical usestrains. for theThe treatment prototypical of systemic amphotericin fungal infectionsB has been since in theclinical 1950s use and for is stillthe antreatment important of optionsystemic in criticalfungal cases.infection Severals since additional the 1950s polyenes, and is still nystatin, an important natamycin, option hamycin, in critical and cases. filipin, Several have additional received regulatory polyenes, approval.nystatin, natamycin, As a class, thehamycin polyenes, and have filipin significant, have received nephrotoxicity regulatory due approval. to their relativelyAs a class, nonselectivethe polyenes mechanismshave significant of ergosterol nephrotoxicity binding due and to pore their formation relatively within nonselective the cell membranemechanism [s6 ,of7]. ergosterol Finally, synthetic binding pyrimidineand pore formation antimetabolites within such the ascell flucytosine membrane interfere [6,7]. Finally, with nucleic synthetic acid biosynthesis,pyrimidine antimetabolites but resistance viasuch point as flucytosine mutations interfere in the fungal with uracilnucleic phosphoribosyltransferase acid biosynthesis, but resistance or cytosine via point deaminase mutations enzymes in the restrictsfungal uracil their applicationphosphoribosyltransferase to combination therapyor cytosine [8]. deaminase enzymes restricts their application to combination therapy [8]. Figure 1. Semisynthetic derivatives of the echinocandin family of natural products approved for Figure 1. Semisynthetic derivatives of the echinocandin family of natural products approved for antifungal therapy. antifungal therapy. Pharmaceuticals 2019, 12, 182 3 of 21 Pharmaceuticals 2019, 12, x FOR PEER REVIEW 3 of 21 Figure 2. Polyene natural products approved for antifungal therapy. Figure 2. Polyene natural products approved for antifungal therapy. Overall, the current drugs have numerous limitations including toxicity, drug–drug interactions, Overall, the current drugs have numerous limitations including toxicity, drug–drug interactions, poor pharmacokinetics, narrow spectrum of activity, and fungistatic versus fungicidal action. These poor pharmacokinetics, narrow spectrum of activity, and fungistatic versus fungicidal action. These inherent liabilities are exacerbated in immunocompromised patients since their immune system cannot inherent liabilities are exacerbated in immunocompromised patients since their immune system effectively assist in the eradication of the infection, thus requiring complex and prolonged treatment cannot effectively assist in the eradication of the infection, thus requiring complex and prolonged regimens [9]. A further alarming trend is the rising incidence of fungal clinical isolates that are resistant treatment regimens [9]. A further alarming trend is the rising incidence of fungal clinical isolates that to the currently used antifungals [10,11]. The scale of the problem is highlighted by the fact that the are resistant to the currently used antifungals [10,11]. The scale of the problem is highlighted by the newest class of approved antifungals, the echinocandins, were actually discovered fifty years ago. fact that the newest class of approved antifungals, the echinocandins, were actually discovered fifty years ago. The American Food and Drug Administration (FDA) has recognized the need for new Pharmaceuticals 2019, 12, 182 4 of 21 ThePharmaceuticals American 2019 Food, 12, andx FOR Drug PEER AdministrationREVIEW (FDA) has recognized the need for new antifungals4 of by 21 placing Candida and Aspergillus on their list of qualifying pathogens [12]. Therapies directed against antifungals by placing Candida and Aspergillus on their list of qualifying pathogens [12]. Therapies these species will benefit from incentives including an additional five-year marketing exclusivity directed against these species will benefit from incentives including an additional five-year besides eligibility for designation as a fast-track drug. marketing exclusivity besides eligibility for designation as a fast-track drug. 2. A Pipeline of Antifungal Natural Product Leads 2. A Pipeline of Antifungal Natural Product Leads While antifungal agents with novel mechanisms of action are in various stages of clinical development,While antifungal their number agents is relatively with novel small mechanisms compared to otherof action therapeutic are in indicationsvarious stages [13]. Aof pipeline clinical