The utility of clinically available antifungals is limited by their narrow spectrum of activity, high toxicity, and emerging resistance. Antifungal drug discovery has always been a challenging area, since fungi and their human host are eukaryotes, making it difficult to identify unique targets for antifungals. Novel antifungals in clinical development include first-in-class agents, new structures for an established target, and formulation modifications to marketed antifungals, in addition to repurposed agents. Membrane interacting peptides and aromatherapy are gaining increased attention in the field. Immunotherapy is another promising treatment option, with antifungal antibodies advancing into clinical trials. Novel targets for antifungal therapy are also being discovered, allowing the design of new promising agents that may overcome the resistance issue. In this mini review, we will summarize the current status of antifungal drug pipelines in clinical stages, and the most recent advancements in preclinical antifungal drug development, with special focus on their chemistry.

Faculty of Pharmacy in Hradec Králové Charles University 50005 Hradec Králové Czech Republic

Zobrazit více v PubMed

Chowdhary A., Tarai B., Singh A., Sharma A. Multidrug-Resistant Candida auris Infections in Critically Ill Coronavirus Disease Patients, India, April–July 2020. Emerg. Infect. Dis. 2020;26:2694–2696. doi: 10.3201/eid2611.203504. PubMed DOI PMC

Boral H., Metin B., Dogen A., Seyedmousavi S., Ilkit M. Overview of selected virulence attributes in Aspergillus fumigants, Candida albicans, Cryptococcus neoformans, Trichophyton rubrum, and Exophiala dermatitidis. Fungal Genet. Biol. 2018;111:92–107. doi: 10.1016/j.fgb.2017.10.008. PubMed DOI

Du H., Bing J., Hu T.R., Ennis C.L., Nobile C.J., Huang G.H. Candida auris: Epidemiology, biology, antifungal resistance, and virulence. PLoS Pathog. 2020;16:e1008921. doi: 10.1371/journal.ppat.1008921. PubMed DOI PMC

Odds F.C., Brown A.J., Gow N.A. Antifungal agents: Mechanisms of action. Trends Microbiol. 2003;11:272–279. doi: 10.1016/S0966-842X(03)00117-3. PubMed DOI

Pienaar E.D., Young T., Holmes H. Interventions for the prevention and management of oropharyngeal candidiasis associated with HIV infection in adults and children. Cochrane Database Syst. Rev. 2010;2010:CD003940. doi: 10.1002/14651858.CD003940.pub3. PubMed DOI

Vermes A., Guchelaar H.J., Dankert J. Flucytosine: A review of its pharmacology, clinical indications, pharmacokinetics, toxicity and drug interactions. J. Antimicrob. Chemother. 2000;46:171–179. doi: 10.1093/jac/46.2.171. PubMed DOI

Emri T., Majoros L., Toth V., Pocsi I. Echinocandins: Production and applications. Appl. Microbiol. Biotechnol. 2013;97:3267–3284. doi: 10.1007/s00253-013-4761-9. PubMed DOI

Maligie M.A., Selitrennikoff C.P. Cryptococcus neoformans resistance to echinocandins: (1,3)beta-glucan synthase activity is sensitive to echinocandins. Antimicrob. Agents Chemother. 2005;49:2851–2856. doi: 10.1128/AAC.49.7.2851-2856.2005. PubMed DOI PMC

Ciaravino V., Coronado D., Lanphear C., Shaikh I., Ruddock W., Chanda S. Tavaborole, a novel boron-containing small molecule for the topical treatment of onychomycosis, is noncarcinogenic in 2-year carcinogenicity studies. Int. J. Toxicol. 2014;33:419–427. doi: 10.1177/1091581814545245. PubMed DOI

Nishikawa H., Sakagami T., Yamada E., Fukuda Y., Hayakawa H., Nomura N., Mitsuyama J., Miyazaki T., Mukae H., Kohno S. T-2307, a novel arylamidine, is transported into Candida albicans nby a high-affinity spermine and spermidine carrier regulated by Agp2. J. Antimicrob. Chemother. 2016;71:1845–1855. doi: 10.1093/jac/dkw095. PubMed DOI

Yamada E., Nishikawa H., Nomura N., Mitsuyama J. T-2307 Shows Efficacy in a Murine Model of Candida glabrata Infection despite In Vitro Trailing Growth Phenomena. Antimicrob. Agents Chemother. 2010;54:3630–3634. doi: 10.1128/AAC.00355-10. PubMed DOI PMC

Wiederhold N.P. Review of T-2307, an Investigational Agent That Causes Collapse of Fungal Mitochondrial Membrane Potential. J. Fungi. 2021;7:130. doi: 10.3390/jof7020130. PubMed DOI PMC

Mann P.A., McLellan C.A., Koseoglu S., Si Q., Kuzmin E., Flattery A., Harris G., Sher X., Murgolo N., Wang H., et al. Chemical Genomics-Based Antifungal Drug Discovery: Targeting Glycosylphosphatidylinositol (GPI) Precursor Biosynthesis. ACS Infect. Dis. 2015;1:59–72. doi: 10.1021/id5000212. PubMed DOI PMC

Nakamoto K., Tsukada I., Tanaka K., Matsukura M., Haneda T., Inoue S., Murai N., Abe S., Ueda N., Miyazaki M., et al. Synthesis and evaluation of novel antifungal agents-quinoline and pyridine amide derivatives. Bioorganic Med. Chem. Lett. 2010;20:4624–4626. doi: 10.1016/j.bmcl.2010.06.005. PubMed DOI

Watanabe N.A., Miyazaki M., Horii T., Sagane K., Tsukahara K., Hata K. E1210, a new broad-spectrum antifungal, suppresses Candida albicans hyphal growth through inhibition of glycosylphosphatidylinositol biosynthesis. Antimicrob. Agents Chemother. 2011;56:960–971. doi: 10.1128/AAC.00731-11. PubMed DOI PMC

Shaw K.J., Ibrahim A.S. Fosmanogepix: A Review of the First-in-Class Broad Spectrum Agent for the Treatment of Invasive Fungal Infections. J. Fungi. 2020;6:239. doi: 10.3390/jof6040239. PubMed DOI PMC

Hector R.F., Pappagianis D. Inhibition of Chitin Synthesis in the Cell-Wall of Coccidioides-Immitis by Polyoxin-D. J. Bacteriol. 1983;154:488–498. doi: 10.1128/jb.154.1.488-498.1983. PubMed DOI PMC

Fortwendel J.R., Juvvadi P.R., Pinchai N., Perfect B.Z., Alspaugh J.A., Perfect J.R., Steinbach W.J. Differential Effects of Inhibiting Chitin and 1,3-beta-D-Glucan Synthesis in Ras and Calcineurin Mutants of Aspergillus fumigatus. Antimicrob. Agents Chemother. 2009;53:476–482. doi: 10.1128/AAC.01154-08. PubMed DOI PMC

Larwood D.J. Nikkomycin Z-Ready to Meet the Promise? J. Fungi. 2020;6:261. doi: 10.3390/jof6040261. PubMed DOI PMC

Oliver J.D., Sibley G., Beckmann N., Dobb K.S., Slater M.J., McEntee L., du Pré S., Livermore J., Bromley M.J., Wiederhold N.P., et al. F901318 represents a novel class of antifungal drug that inhibits dihydroorotate dehydrogenase. Proc. Natl. Acad. Sci. USA. 2016;113:12809–12814. doi: 10.1073/pnas.1608304113. PubMed DOI PMC

Negri C.E., Johnson A., McEntee L., Box H., Whalley S., Schwartz J.A., Ramos-Martín V., Livermore J., Kolamunnage-Dona R., Colombo A.L., et al. Pharmacodynamics of the Novel Antifungal Agent F901318 for Acute Sinopulmonary Aspergillosis Caused by Aspergillus flavus. J. Infect. Dis. 2018;217:1118–1127. doi: 10.1093/infdis/jix479. PubMed DOI PMC

Wiederhold N.P. Review of the Novel Investigational Antifungal Olorofim. J. Fungi. 2020;6:122. doi: 10.3390/jof6030122. PubMed DOI PMC

Nakamura I., Kanasaki R., Yoshikawa K., Furukawa S., Fujie A., Hamamoto H., Sekimizu K. Discovery of a new antifungal agent ASP2397 using a silkworm model of Aspergillus fumigatus infection. J. Antibiot. (Tokyo) 2017;70:41–44. doi: 10.1038/ja.2016.106. PubMed DOI

Nakamura I., Ohsumi K., Takeda S., Katsumata K., Matsumoto S., Akamatsu S., Mitori H., Nakai T. ASP2397 Is a Novel Natural Compound That Exhibits Rapid and Potent Fungicidal Activity against Aspergillus Species through a Specific Transporter. Antimicrob. Agents Chemother. 2019;63:e02689-18. doi: 10.1128/AAC.02689-18. PubMed DOI PMC

Ikai K., Takesako K., Shiomi K., Moriguchi M., Umeda Y., Yamamoto J., Kato I., Naganawa H. Structure of aureobasidin A. J. Antibiot. 1991;44:925–933. doi: 10.7164/antibiotics.44.925. PubMed DOI

Alqaisi A., Mbekeani A.J., Llorens M.B., Elhammer A.P., Denny P.W. The antifungal Aureobasidin A and an analogue are active against the protozoan parasite Toxoplasma gondii but do not inhibit sphingolipid biosynthesis—Corrigendum. Parasitology. 2018;145:156. doi: 10.1017/S0031182017000877. PubMed DOI PMC

Kurome T., Inoue T., Takesako K., Kato I., Inami K., Shiba T. Syntheses of antifungal aureobasidin A analogs with alkyl chains for structure-activity relationship. J. Antibiot. 1998;51:359–367. doi: 10.7164/antibiotics.51.359. PubMed DOI

Pfaller M.A., Messer S.A., Georgopapadakou N., Martell L.A., Besterman J.M., Diekema D.J. Activity of MGCD290, a Hos2 Histone Deacetylase Inhibitor, in Combination with Azole Antifungals against Opportunistic Fungal Pathogens. J. Clin. Microbiol. 2009;47:3797–3804. doi: 10.1128/JCM.00618-09. PubMed DOI PMC

Cowen L.E. The fungal Achilles’ heel: Targeting Hsp90 to cripple fungal pathogens. Curr. Opin. Microbiol. 2013;16:377–384. doi: 10.1016/j.mib.2013.03.005. PubMed DOI

Pfaller M.A., Rhomberg P.R., Messer S.A., Castanheira M. In vitro activity of a Hos2 deacetylase inhibitor, MGCD290, in combination with echinocandins against echinocandin-resistant Candida species. Diagn. Microbiol. Infect. Dis. 2015;81:259–263. doi: 10.1016/j.diagmicrobio.2014.11.008. PubMed DOI

Hoekstra W.J., Garvey E.P., Moore W.R., Rafferty S.W., Yates C.M., Schotzinger R.J. Design and optimization of highly-selective fungal CYP51 inhibitors. Bioorg. Med. Chem. Lett. 2014;24:3455–3458. doi: 10.1016/j.bmcl.2014.05.068. PubMed DOI

Zhang J.X., Li L.P., Lv Q.Z., Yan L., Wang Y., Jiang Y.Y. The Fungal CYP51s: Their Functions, Structures, Related Drug Resistance, and Inhibitors. Front. Microbiol. 2019;10:691. doi: 10.3389/fmicb.2019.00691. PubMed DOI PMC

Warrilow A.G.S., Parker J.E., Price C.L., Nes W.D., Garvey E.P., Hoekstra W.J., Schotzinger R.J., Kelly D.E., Kelly S.L. The Investigational Drug VT-1129 Is a Highly Potent Inhibitor of Cryptococcus Species CYP51 but Only Weakly Inhibits the Human Enzyme. Antimicrob. Agents Chemother. 2016;60:4530–4538. doi: 10.1128/AAC.00349-16. PubMed DOI PMC

Garvey E.P., Hoekstra W.J., Schotzinger R.J., Sobel J.D., Lilly E.A., Fidel P.L., Jr. Efficacy of the Clinical Agent VT-1161 against Fluconazole-Sensitive and -Resistant Candida albicans in a Murine Model of Vaginal Candidiasis. Antimicrob. Agents Chemother. 2015;59:5567–5573. doi: 10.1128/AAC.00185-15. PubMed DOI PMC

Wiederhold N.P., Lockhart S.R., Najvar L.K., Berkow E.L., Jaramillo R., Olivo M., Garvey E.P., Yates C.M., Schotzinger R.J., Catano G., et al. The Fungal Cyp51-Specific Inhibitor VT-1598 Demonstrates In Vitro and In Vivo Activity against Candida auris. Antimicrob. Agents Chemother. 2019;63:e02233-18. doi: 10.1128/AAC.02233-18. PubMed DOI PMC

Bowman J.C., Hicks P.S., Kurtz M.B., Rosen H., Schmatz D.M., Liberator P.A., Douglas C.M. The antifungal echinocandin caspofungin acetate kills growing cells of Aspergillus fumigatus in vitro. Antimicrob. Agents Chemother. 2002;46:3001–3012. doi: 10.1128/AAC.46.9.3001-3012.2002. PubMed DOI PMC

Odds F.C. Drug evaluation: BAL-8557—A novel broad-spectrum triazole antifungal. Curr. Opin. Investig. Drugs. 2006;7:766–772. PubMed

Schmitt-Hoffmann A., Roos B., Heep M., Schleimer M., Weidekamm E., Brown T., Roehrle M., Beglinger C. Single-ascending-dose pharmacokinetics and safety of the novel broad-spectrum antifungal triazole BAL4815 after intravenous infusions (50, 100, and 200 milligrams) and oral administrations (100, 200, and 400 milligrams) of its prodrug, BAL8557, in healthy volunteers. Antimicrob. Agents Chemother. 2006;50:279–285. PubMed PMC

Bartroli J., Turmo E., Algueró M., Boncompte E., Vericat M.L., Conte L., Ramis J., Merlos M., García-Rafanell J., Forn J. New azole antifungals. 2. Synthesis and antifungal activity of heterocyclecarboxamide derivatives of 3-amino-2-aryl-1-azolyl-2-butanol. J. Med. Chem. 1998;41:1855–1868. doi: 10.1021/jm970726e. PubMed DOI

Sun N., Xie Y., Sheng C., Cao Y., Zhang W., Chen H., Fan G. In vivo pharmacokinetics and in vitro antifungal activity of iodiconazole, a new triazole, determined by microdialysis sampling. Int. J. Antimicrob. Agents. 2013;41:229–235. doi: 10.1016/j.ijantimicag.2012.10.020. PubMed DOI

Brautaset T., Sletta H., Degnes K.F., Sekurova O.N., Bakke I., Volokhan O., Andreassen T., Ellingsen T.E., Zotchev S.B. New nystatin-related antifungal polyene macrolides with altered polyol region generated via biosynthetic engineering of Streptomyces noursei. Appl. Environ. Microbiol. 2011;77:6636–6643. doi: 10.1128/AEM.05780-11. PubMed DOI PMC

Krishnan B.R., James K.D., Polowy K., Bryant B.J., Vaidya A., Smith S., Laudeman C.P. CD101, a novel echinocandin with exceptional stability properties and enhanced aqueous solubility. J. Antibiot. 2017;70:130–135. doi: 10.1038/ja.2016.89. PubMed DOI

Ong V., James K.D., Smith S., Krishnan B.R. Pharmacokinetics of the Novel Echinocandin CD101 in Multiple Animal Species. Antimicrob. Agents Chemother. 2017;61:e01626-16. doi: 10.1128/AAC.01626-16. PubMed DOI PMC

Zhao Y., Prideaux B., Nagasaki Y., Lee M.H., Chen P.Y., Blanc L., Ho H., Clancy C.J., Nguyen M.H., Dartois V., et al. Unraveling Drug Penetration of Echinocandin Antifungals at the Site of Infection in an Intra-abdominal Abscess Model. Antimicrob. Agents Chemother. 2017;61:e01009-17. doi: 10.1128/AAC.01009-17. PubMed DOI PMC

Abuhelwa A.Y., Foster D.J.R., Mudge S., Hayes D., Upton R.N. Population Pharmacokinetic Modeling of Itraconazole and Hydroxyitraconazole for Oral SUBA-Itraconazole and Sporanox Capsule Formulations in Healthy Subjects in Fed and Fasted States. Antimicrob. Agents Chemother. 2015;59:5681–5696. doi: 10.1128/AAC.00973-15. PubMed DOI PMC

Gupta A.K., Surprenant M.S., Kempers S.E., Pariser D.M., Rensfeldt K., Tavakkol A. Efficacy and safety of topical terbinafine 10% solution (MOB-015) in the treatment of mild to moderate distal subungual onychomycosis: A randomized, multicenter, double-blind, vehicle-controlled phase 3 study. J. Am. Acad. Dermatol. 2021;85:95–104. doi: 10.1016/j.jaad.2020.06.055. PubMed DOI

Pinna A., Donadu M.G., Usai D., Dore S., Boscia F., Zanetti S. In Vitro Antimicrobial Activity of a New Ophthalmic Solution Containing Hexamidine Diisethionate 0.05% (Keratosept) Cornea. 2020;39:1415–1418. doi: 10.1097/ICO.0000000000002375. PubMed DOI

Pinna A., Donadu M.G., Usai D., Dore S., D’Amico-Ricci G., Boscia F., Zanetti S. In vitro antimicrobial activity of a new ophthalmic solution containing povidone-iodine 0.6% (IODIM (R)) Acta Ophthalmol. 2020;98:E178–E180. doi: 10.1111/aos.14243. PubMed DOI

Santangelo R., Paderu P., Delmas G., Chen Z.W., Mannino R., Zarif L., Perlin D.S. Efficacy of oral cochleate-amphotericin B in a mouse model of systemic candidiasis. Antimicrob. Agents Chemother. 2000;44:2356–2360. doi: 10.1128/AAC.44.9.2356-2360.2000. PubMed DOI PMC

Gasser G., Metzler-Nolte N. The potential of organometallic complexes in medicinal chemistry. Curr. Opin. Chem. Biol. 2012;16:84–91. doi: 10.1016/j.cbpa.2012.01.013. PubMed DOI

Kljun J., Scott A.J., Rizner T.L., Keiser J., Turel I. Synthesis and Biological Evaluation of Organoruthenium Complexes with Azole Antifungal Agents. First Crystal Structure of a Tioconazole Metal Complex. Organometallics. 2014;33:1594–1601. doi: 10.1021/om401096y. DOI

Stevanović N.L., Aleksic I., Kljun J., Bogojevic S.S., Veselinovic A., Nikodinovic-Runic J., Turel I., Djuran M.I., Glišić B.Đ. Copper(II) and Zinc(II) Complexes with the Clinically Used Fluconazole: Comparison of Antifungal Activity and Therapeutic Potential. Pharmaceuticals. 2021;14:24. doi: 10.3390/ph14010024. PubMed DOI PMC

Andrejević T.P., Aleksic I., Počkaj M., Kljun J., Milivojevic D., Stevanović N.L., Nikodinovic-Runic J., Turel I., Djuran M.I., Glišić B.Đ. Tailoring copper(II) complexes with pyridine-4,5-dicarboxylate esters for anti-Candida activity. Dalton Trans. 2021;50:2627–2638. doi: 10.1039/D0DT04061D. PubMed DOI

Savic N.D., Vojnovic S., Glisic B.Ð., Crochet A., Pavic A., Janjic G.V., Pekmezovic M., Opsenica I.M., Fromm K.M., Nikodinovic-Runic J., et al. Mononuclear silver(I) complexes with 1,7-phenanthroline as potent inhibitors of Candida growth. Eur. J. Med. Chem. 2018;156:760–773. doi: 10.1016/j.ejmech.2018.07.049. PubMed DOI

Polvi E.J., Averette A.F., Lee S.C., Kim T., Bahn Y., Veri A.O., Robbins N., Heitman J., Cowen L.E. Metal Chelation as a Powerful Strategy to Probe Cellular Circuitry Governing Fungal Drug Resistance and Morphogenesis. PLoS Genet. 2016;12:e1006350. doi: 10.1371/journal.pgen.1006350. PubMed DOI PMC

Lin Y., Betts H., Keller S., Cariou K., Gasser G. Recent developments of metal-based compounds against fungal pathogens. Chem. Soc. Rev. 2021;50:10346–10402. doi: 10.1039/D0CS00945H. PubMed DOI

Nishikawa H., Fukuda Y., Mitsuyama J., Tashiro M., Tanaka A., Takazono T., Saijo T., Yamamoto K., Nakamura S., Imamura Y., et al. In vitro and in vivo antifungal activities of T-2307, a novel arylamidine, against Cryptococcus gattii: An emerging fungal pathogen. J. Antimicrob. Chemother. 2017;72:1709–1713. doi: 10.1093/jac/dkx020. PubMed DOI PMC

Sun N., Wen J., Lu G., Hong Z., Fan G., Wu Y., Sheng C., Zhang W. An ultra-fast LC method for the determination of iodiconazole in microdialysis samples and its application in the calibration of laboratory-made linear probes. J. Pharm. Biomed. Anal. 2010;51:248–251. doi: 10.1016/j.jpba.2009.07.016. PubMed DOI

Ravu R.R., Jacob M.R., Khan S.I., Wang M., Cao L., Agarwal A.K., Clark A.M., Li X. Synthesis and Antifungal Activity Evaluation of Phloeodictine Analogues. J. Nat. Prod. 2021;84:2129–2137. doi: 10.1021/acs.jnatprod.1c00116. PubMed DOI

Choi J.W., Lee K., Kim S., Lee Y.R., Kim H.J., Seo K.J., Lee M.H., Yeon S.K., Jang B.K., Park S.J., et al. Optimization and Evaluation of Novel Antifungal Agents for the Treatment of Fungal Infection. J. Med. Chem. 2021;64:15912–15935. doi: 10.1021/acs.jmedchem.1c01299. PubMed DOI

Kato I., Ukai Y., Kondo N., Nozu K., Kimura C., Hashimoto K., Mizusawa E., Maki H., Naito A., Kawai M. Identification of Thiazoyl Guanidine Derivatives as Novel Antifungal Agents Inhibiting Ergosterol Biosynthesis for Treatment of Invasive Fungal Infections. J. Med. Chem. 2021;64:10482–10496. PubMed

Li Z., Tu J., Han G.Y., Liu N., Sheng C.Q. Novel Carboline Fungal Histone Deacetylase (HDAC) Inhibitors for Combinational Treatment of Azole-Resistant Candidiasis. J. Med. Chem. 2021;64:1116–1126. doi: 10.1021/acs.jmedchem.0c01763. PubMed DOI

Krishnamurthy S., Plaine A., Albert J., Prasad T., Prasad R., Ernst J.F. Dosage-dependent functions of fatty acid desaturase Ole1p in growth and morphogenesis of Candida albicans. Microbiology-Sgm. 2004;150:1991–2003. doi: 10.1099/mic.0.27029-0. PubMed DOI

DeJarnette C., Meyer C.J., Jenner A.R., Butts A., Peters T., Cheramie M.N., Phelps G.A., Vita N.A., Loudon-Hossler V.C., Lee R.E., et al. Identification of Inhibitors of Fungal Fatty Acid Biosynthesis. ACS Infect. Dis. 2021;7:3210–3223. doi: 10.1021/acsinfecdis.1c00404. PubMed DOI PMC

Lowes D.J., Miao J., Al-Waqfi R.A., Avad K.A., Hevener K.E., Peters B.M. Identification of Dual-Target Compounds with Anti-fungal and Anti-NLRP3 Inflammasome Activity. ACS Infect. Dis. 2021;7:2522–2535. doi: 10.1021/acsinfecdis.1c00270. PubMed DOI PMC

Pue N., Guddat L.W. Acetohydroxyacid Synthase: A Target for Antimicrobial Drug Discovery. Curr. Pharm. Des. 2014;20:740–753. doi: 10.2174/13816128113199990009. PubMed DOI

Camilli G., Griffiths J.S., Ho J., Richardson J.P., Naglik J.R. Some like it hot: Candida activation of inflammasomes. PLoS Pathog. 2020;16:e1008975. doi: 10.1371/journal.ppat.1008975. PubMed DOI PMC

Teixeira V., Feio M.J., Bastos M. Role of lipids in the interaction of antimicrobial peptides with membranes. Prog. Lipid Res. 2012;51:149–177. doi: 10.1016/j.plipres.2011.12.005. PubMed DOI

Gomes B., Augusto M.T., Felício M.R., Hollmann A., Franco O.L., Gonçalves S., Santos N.C. Designing improved active peptides for therapeutic approaches against infectious diseases. Biotechnol. Adv. 2018;36:415–429. doi: 10.1016/j.biotechadv.2018.01.004. PubMed DOI

Struyfs C., Cammue B.P.A., Thevissen K. Membrane-Interacting Antifungal Peptides. Front. Cell Dev. Biol. 2021;9:649875. doi: 10.3389/fcell.2021.649875. PubMed DOI PMC

Donadu M.G., Peralta-Ruiz Y., Usai D., Maggio F., Molina-Hernandez J.B., Rizzo D., Bussu F., Rubino S., Zanetti S., Paparella A. Colombian Essential Oil of Ruta graveolens against Nosocomial Antifungal Resistant Candida Strains. J. Fungi. 2021;7:383. doi: 10.3390/jof7050383. PubMed DOI PMC

Donadu M.G., Usai D., Marchetti M., Usai M., Mazzarello V., Molicotti P., Montesu M.A., Delogu G., Zanetti S. Antifungal activity of oils macerates of North Sardinia plants against Candida species isolated from clinical patients with candidiasis. Nat. Prod. Res. 2020;34:3280–3284. doi: 10.1080/14786419.2018.1557175. PubMed DOI

Bua A., Usai D., Donadu M.G., Delgado Ospina J., Paparella A., Chaves-Lopez C., Serio A., Rossi C., Zanetti S., Molicotti P. Antimicrobial activity of Austroeupatorium inulaefolium (HBK) against intracellular and extracellular organisms. Nat. Prod. Res. 2018;32:2869–2871. doi: 10.1080/14786419.2017.1385014. PubMed DOI

Dolan K., Montgomery S., Buchheit B., DiDone L., Wellingtone M., Krysan D.J. Antifungal Activity of Tamoxifen: In Vitro and In Vivo Activities and Mechanistic Characterization. Antimicrob. Agents Chemother. 2009;53:3337–3346. doi: 10.1128/AAC.01564-08. PubMed DOI PMC

Koselny K., Green J., DiDone L., Halterman J.P., Fothergill A.W., Wiederhold N.P., Patterson T.F., Cushion M.T., Rappelye C., Wellington M., et al. The Celecoxib Derivative AR-12 Has Broad-Spectrum Antifungal Activity In Vitro and Improves the Activity of Fluconazole in a Murine Model of Cryptococcosis. Antimicrob. Agents Chemother. 2016;60:7115–7127. doi: 10.1128/AAC.01061-16. PubMed DOI PMC

Posch W., Wilflingseder D., Lass-Florl C. Immunotherapy as an Antifungal Strategy in Immune Compromised Hosts. Curr. Clin. Microbiol. Rep. 2020;7:57–66. doi: 10.1007/s40588-020-00141-9. DOI

Rachini A., Pietrella D., Lupo P., Torosantucci A., Chiani P., Bromuro C., Proietti C., Bistoni F., Cassone A., Vecchiarelli A. An anti-beta-glucan monoclonal antibody inhibits growth and capsule formation of Cryptococcus neofonnans in vitro and exerts therapeutic, anticryptococcal activity in vivo. Infect. Immun. 2007;75:5085–5094. doi: 10.1128/IAI.00278-07. PubMed DOI PMC

Mambro T.D., Vanzolini T., Bruscolini P., Perez-Gaviro S., Marra E., Roscilli G., Bianchi M., Fraternale A., Schiavano G.F., Canonico B., et al. A new humanized antibody is effective against pathogenic fungi in vitro. Sci. Rep. 2021;11:19500. doi: 10.1038/s41598-021-98659-5. PubMed DOI PMC

Nosanchuk J.D., Dadachova E. Radioimmunotherapy of fungal diseases: The therapeutic potential of cytocidal radiation delivered by antibody targeting fungal cell surface antigens. Front. Microbiol. 2012;3:283. doi: 10.3389/fmicb.2011.00283. PubMed DOI PMC

Heung L.J., Luberto C., Del Poeta M. Role of sphingolipids in microbial pathogenesis. Infect. Immun. 2006;74:28–39. doi: 10.1128/IAI.74.1.28-39.2006. PubMed DOI PMC

Levery S.B., Momany M., Lindsey R., Toledo M.S., Shayman J.A., Fuller M., Brooks K., Doong R.L., Straus A.H., Takahashi H.K. Disruption of the glucosylceramide biosynthetic pathway in Aspergillus nidulans and Aspergillus fumigatus by inhibitors of UDP-Glc: Ceramide glucosyltransferase strongly affects spore germination, cell cycle, and hyphal growth (vol 525, pg 59, 2002) Febs Lett. 2002;526:151. doi: 10.1016/S0014-5793(02)03144-7. PubMed DOI

Rittershaus P.C., Kechichian T.B., Allegood J.C., Merrill A.H., Jr., Hennig M., Luberto C., Del Poeta M. Glucosylceramide synthase is an essential regulator of pathogenicity of Cryptococcus neoformans. J. Clin. Investig. 2006;116:1651–1659. doi: 10.1172/JCI27890. PubMed DOI PMC

Mandala S.M., Thornton R.A., Frommer B.R., Curotto J.E., Rozdilsky W., Kurtz M.B., Giacobbe R.A., Bills G.F., Cabello M.A., Martín I. The Discovery of Australifungin, a Novel Inhibitor of Sphinganine N-Acyltransferase from Sporormiella-Australis—Producing Organism, Fermentation, Isolation, and Biological-Activity. J. Antibiot. 1995;48:349–356. doi: 10.7164/antibiotics.48.349. PubMed DOI

Achenbach H., Mühlenfeld A., Fauth U., Zähner H. The galbonolides. Novel, powerful antifungal macrolides from Streptomyces galbus ssp. eurythermus. Ann. N. Y. Acad. Sci. 1988;544:128–140. doi: 10.1111/j.1749-6632.1988.tb40396.x. PubMed DOI

Mora V., Rellaa A., Farnouda A.M., Singha A., Munshia M., Bryana A., Naseema S., Konopkaa J.B., Ojimab I., Bullesbachc E., et al. Identification of a New Class of Antifungals Targeting the Synthesis of Fungal Sphingolipids. Mbio. 2015;6:e00647-15. doi: 10.1128/mBio.00647-15. PubMed DOI PMC

Kryštůfek R., Šácha P., Starková J., Brynda J., Hradilek M., Tloušt’ová E., Grzymska J., Rut W., Boucher M.J., Drąg M., et al. Re-emerging Aspartic Protease Targets: Examining Cryptococcus neoformans Major Aspartyl Peptidase 1 as a Target for Antifungal Drug Discovery. J. Med. Chem. 2021;64:6706–6719. doi: 10.1021/acs.jmedchem.0c02177. PubMed DOI PMC