We reviewed the licensed antifungal drugs and summarized their mechanisms of action, pharmacological profiles, and susceptibility to specific fungi. Approved antimycotics inhibit 1,3-β-d-glucan synthase, lanosterol 14-α-demethylase, protein, and deoxyribonucleic acid biosynthesis, or sequestrate ergosterol. Their most severe side effects are hepatotoxicity, nephrotoxicity, and myelotoxicity. Whereas triazoles exhibit the most significant drug-drug interactions, echinocandins exhibit almost none. The antifungal resistance may be developed across most pathogens and includes drug target overexpression, efflux pump activation, and amino acid substitution. The experimental antifungal drugs in clinical trials are also reviewed. Siderophores in the Trojan horse approach or the application of siderophore biosynthesis enzyme inhibitors represent the most promising emerging antifungal therapies.

Institute of Microbiology of the Czech Academy of Sciences Vídeňská 1083 14220 Prague Czech Republic

Zobrazit více v PubMed

Pianalto K., Alspaugh J.A. New Horizons in Antifungal Therapy. J. Fungi. 2016;2:26. doi: 10.3390/jof2040026. PubMed DOI PMC

Hidden Crisis: How 150 People Die Every Hour from Fungal Infection While the World Turns a Blind Eye. [(accessed on 3 March 2020)]; Available online: https://www.gaffi.org/wp-content/uploads/GAFFI-Leaflet-June-2016-DWD-hidden-crisis.pdf.

Bongomin F., Gago S., Oladele R.O., Denning D.W. Global and Multi-National Prevalence of Fungal Diseases—Estimate Precision. J. Fungi. 2017;3:57. doi: 10.3390/jof3040057. PubMed DOI PMC

Prakash H., Chakrabarti A. Global Epidemiology of Mucormycosis. J. Fungi. 2019;5:26. doi: 10.3390/jof5010026. PubMed DOI PMC

Brown G.D., Denning D.W., Gow N., Levitz S.M., Netea M., White T.C. Hidden Killers: Human Fungal Infections. Sci. Transl. Med. 2012;4:165rv13. doi: 10.1126/scitranslmed.3004404. PubMed DOI

Guarro J., Kantarcioglu A.S., Horré R., Rodríguez-Tudela J.L., Estrella M.C., Berenguer J., De Hoog G.S. Scedosporium apiospermum: Changing clinical spectrum of a therapy-refractory opportunist. Med. Mycol. 2006;44:295–327. doi: 10.1080/13693780600752507. PubMed DOI

Nucci M., Anaissie E. Fusarium Infections in Immunocompromised Patients. Clin. Microbiol. Rev. 2007;20:695–704. doi: 10.1128/CMR.00014-07. PubMed DOI PMC

Carmona E.M., Limper A.H. Overview of Treatment Approaches for Fungal Infections. Clin. Chest Med. 2017;38:393–402. doi: 10.1016/j.ccm.2017.04.003. PubMed DOI

Kumar A., Zarychanski R., Pisipati A., Kumar A., Kethireddy S., Bow E.J. Fungicidal versus fungistatic therapy of invasiveCandidainfection in non-neutropenic adults: A meta-analysis. Mycology. 2018;9:116–128. doi: 10.1080/21501203.2017.1421592. PubMed DOI PMC

Meletiadis J., Antachopoulos C., Stergiopoulou T., Pournaras S., Roilides E., Walsh T.J. Differential Fungicidal Activities of Amphotericin B and Voriconazole against Aspergillus Species Determined by Microbroth Methodology. Antimicrob. Agents Chemother. 2007;51:3329–3337. doi: 10.1128/AAC.00345-07. PubMed DOI PMC

Geißel B., Loiko V., Klugherz I., Zhu Z., Wagener N., Kurzai O., Hondel C.A.M.J.J.V.D., Wagener J. Azole-induced cell wall carbohydrate patches kill Aspergillus fumigatus. Nat. Commun. 2018;9:3098. doi: 10.1038/s41467-018-05497-7. PubMed DOI PMC

Patil A., Majumdar S. Echinocandins in antifungal pharmacotherapy. J. Pharm. Pharmacol. 2017;69:1635–1660. doi: 10.1111/jphp.12780. PubMed DOI

Revie N.M., Iyer K.R., Robbins N., Cowen L. Antifungal drug resistance: Evolution, mechanisms and impact. Curr. Opin. Microbiol. 2018;45:70–76. doi: 10.1016/j.mib.2018.02.005. PubMed DOI PMC

Ten Threats to Global Health in 2019. [(accessed on 3 June 2019)]; Available online: https://www.who.int/emergencies/ten-threats-to-global-health-in-2019.

Ahmad S., Bhattacharya D., Kar S., Ranganathan A., Van Kaer L., Das G. Curcumin Nanoparticles Enhance Mycobacterium bovis BCG Vaccine Efficacy by Modulating Host Immune Responses. Infect. Immun. 2019;87:1–33. doi: 10.1128/IAI.00291-19. PubMed DOI PMC

Scriven J.E., Tenforde M.W., Levitz S.M., Jarvis J.N. Modulating host immune responses to fight invasive fungal infections. Curr. Opin. Microbiol. 2017;40:95–103. doi: 10.1016/j.mib.2017.10.018. PubMed DOI PMC

van de Sande W., Vonk A.G. Mycovirus therapy for invasive pulmonary aspergillosis? Med. Mycol. 2019;57:S179–S188. doi: 10.1093/mmy/myy073. PubMed DOI

Nerva L., Chitarra W., Siciliano I., Gaiotti F., Ciuffo M., Forgia M., Varese G.C., Turina M. Mycoviruses mediate mycotoxin regulation in Aspergillus ochraceus. Environ. Microbiol. 2018;21:1957–1968. doi: 10.1111/1462-2920.14436. PubMed DOI

Zotchev S.B. Polyene macrolide antibiotics and their applications in human therapy. Curr. Med. Chem. 2003;10:211–223. doi: 10.2174/0929867033368448. 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

Ping B., Zhu Y., Gao Y., Yue C., Wu B. Second- versus first-generation azoles for antifungal prophylaxis in hematology patients: A systematic review and meta-analysis. Ann. Hematol. 2013;92:831–839. doi: 10.1007/s00277-013-1693-5. PubMed DOI

Livengood S.J., Drew R.H., Perfect J.R. Combination Therapy for Invasive Fungal Infections. Curr. Fungal Infect. Rep. 2020;14:40–49. doi: 10.1007/s12281-020-00369-4. DOI

Mesa-Arango A.C., Scorzoni L., Zaragoza O. It only takes one to do many jobs: Amphotericin B as antifungal and immunomodulatory drug. Front. Microbiol. 2012;3:1–10. doi: 10.3389/fmicb.2012.00286. PubMed DOI PMC

Tevyashova A.N., Olsufyeva E., Solovieva S.E., Printsevskaya S.S., Reznikova M.I., Trenin A.S., Galatenko O.A., Treshalin I.D., Pereverzeva E.R., Mirchink E.P., et al. Structure-Antifungal Activity Relationships of Polyene Antibiotics of the Amphotericin B Group. Antimicrob. Agents Chemother. 2013;57:3815–3822. doi: 10.1128/AAC.00270-13. PubMed DOI PMC

Parker W.B. Enzymology of Purine and Pyrimidine Antimetabolites Used in the Treatment of Cancer. Chem. Rev. 2009;109:2880–2893. doi: 10.1021/cr900028p. PubMed DOI PMC

Sagatova A.A., Keniya M.V., Wilson R.K., Monk B.C., Tyndall J. Structural Insights into Binding of the Antifungal Drug Fluconazole to Saccharomyces cerevisiae Lanosterol 14α-Demethylase. Antimicrob. Agents Chemother. 2015;59:4982–4989. doi: 10.1128/AAC.00925-15. PubMed DOI PMC

Liu J., Balasubramanian M.K. 1,3-beta-Glucan synthase: A useful target for antifungal drugs. Curr. Drug Target Infect. Disord. 2001;1:159–169. doi: 10.2174/1568005014606107. PubMed DOI

Yao J., Liu H., Zhou T., Chen H., Miao Z., Sheng C., Zhang W. Total synthesis and structure–activity relationships of new echinocandin-like antifungal cyclolipohexapeptides. Eur. J. Med. Chem. 2012;50:196–208. doi: 10.1016/j.ejmech.2012.01.054. PubMed DOI

Hamill R.J. Amphotericin B Formulations: A Comparative Review of Efficacy and Toxicity. Drugs. 2013;73:919–934. doi: 10.1007/s40265-013-0069-4. PubMed DOI

Momparler R.L. Optimization of cytarabine (ARA-C) therapy for acute myeloid leukemia. Exp. Hematol. Oncol. 2013;2:20. doi: 10.1186/2162-3619-2-20. PubMed DOI PMC

Nett J.E., Andes D.R. Antifungal Agents. Infect. Dis. Clin. North Am. 2016;30:51–83. doi: 10.1016/j.idc.2015.10.012. PubMed DOI

Debruyne D., Ryckelynck J.-P. Clinical Pharmacokinetics of Fluconazole. Clin. Pharmacokinet. 1993;24:10–27. doi: 10.2165/00003088-199324010-00002. PubMed DOI

Heykants J., Van Peer A., Van De Velde V., Van Rooy P., Meuldermans W., Lavrijsen K., Woestenborghs R., Van Cutsem J., Cauwenbergh G. The Clinical Pharmacokinetics of Itraconazole: An Overview. Mycoses. 1989;32:67–87. doi: 10.1111/j.1439-0507.1989.tb02296.x. PubMed DOI

Salavert M., Jarque I., Zaragoza R., Gobernado M. Voriconazole in the management of nosocomial invasive fungal infections. Ther. Clin. Risk Manag. 2006;2:129–157. PubMed PMC

Li Y., Theuretzbacher U., Clancy C.J., Nguyen M.H., Derendorf H., Derendorf H. Pharmacokinetic/Pharmacodynamic Profile of Posaconazole. Clin. Pharmacokinet. 2010;49:379–396. doi: 10.2165/11319340-000000000-00000. PubMed DOI

Rybak J.M., Marx K.R., Nishimoto A.T., Rogers P.D. Isavuconazole: Pharmacology, Pharmacodynamics, and Current Clinical Experience with a New Triazole Antifungal Agent. Pharmacother. J. Hum. Pharmacol. Drug Ther. 2015;35:1037–1051. doi: 10.1002/phar.1652. PubMed DOI

Kofla G., Ruhnke M. Pharmacology and metabolism of anidulafungin, caspofungin and micafungin in the treatment of invasive candidosis—review of the literature. Eur. J. Med Res. 2011;16:159–166. doi: 10.1186/2047-783X-16-4-159. PubMed DOI PMC

Bellmann R., Smuszkiewicz P. Pharmacokinetics of antifungal drugs: Practical implications for optimized treatment of patients. Infection. 2017;45:737–779. doi: 10.1007/s15010-017-1042-z. PubMed DOI PMC

ERAXIS Product Monograph Anidulafungin for Injection 100 mg/vial. [(accessed on 28 February 2020)]; Available online: https://www.pfizer.ca/sites/default/files/201710/ERAXIS_PM_E_176889_14Oct2014.pdf.

CANDIDAS Product Monograph Caspofungin for Injection 50 mg/vial, 70 mg/vial. [(accessed on 28 February 2020)]; Available online: https://www.merck.ca/static/pdf/CANCIDAS-PM_E.pdf.

Mycamine Product Monograph Micafungin Sodium for Injection 50 mg and 100 mg/vial. [(accessed on 28 February 2020)]; Available online: https://pdf.hres.ca/dpd_pm/00024563.PDF.

Bersani I., Piersigilli F., Goffredo B.M., Santisi A., Cairoli S., Ronchetti M.P., Auriti C. Antifungal Drugs for Invasive Candida Infections (ICI) in Neonates: Future Perspectives. Front. Pediatr. 2019;7:375. doi: 10.3389/fped.2019.00375. PubMed DOI PMC

Warris A., Lehrnbecher T., Roilides E., Castagnola E., Bruggemann R.J., Groll A.H. ESCMID-ECMM guideline: Diagnosis and management of invasive aspergillosis in neonates and children. Clin. Microbiol. Infect. 2019;25:1096–1113. doi: 10.1016/j.cmi.2019.05.019. PubMed DOI

Cornely O.A., Bassetti M., Calandra T., Garbino J., Kullberg B., Lortholary O., Meersseman W., Akova M., Arendrup M.C., Arikan-Akdagli S., et al. ESCMID This guideline was presented in part at ECCMID 2011. European Society for Clinical Microbiology and Infectious Diseases. guideline for the diagnosis and management of Candida diseases 2012: Non-neutropenic adult patients. Clin. Microbiol. Infect. 2012;18:19–37. doi: 10.1111/1469-0691.12039. PubMed DOI

Ullmann A., Aguado J., Arikan-Akdagli S., Denning D., Groll A., Lagrou K., Lass-Flörl C., Lewis R., Munoz P., Verweij P.E., et al. Diagnosis and management of Aspergillus diseases: Executive summary of the 2017 ESCMID-ECMM-ERS guideline. Clin. Microbiol. Infect. 2018;24:e1–e38. doi: 10.1016/j.cmi.2018.01.002. PubMed DOI

Pilmis B., Jullien V., Sobel J., Lecuit M., Lortholary O., Charlier C. Antifungal drugs during pregnancy: An updated review. J. Antimicrob. Chemother. 2014;70:14–22. doi: 10.1093/jac/dku355. PubMed DOI

Payne K.D., Hall R. Dosing of Antifungal Agents in Obese People. Expert Rev. Anti Infect. Ther. 2015;14:257–267. doi: 10.1586/14787210.2016.1128822. PubMed DOI

Lestner J., Smith P.B., Cohen-Wolkowiez M., Benjamin D.K., Hope W. Antifungal agents and therapy for infants and children with invasive fungal infections: A pharmacological perspective. Br. J. Clin. Pharmacol. 2012;75:1381–1395. doi: 10.1111/bcp.12025. PubMed DOI PMC

EUCAST. [(accessed on 24 January 2020)]; Available online: http://www.eucast.org/

CLSI. [(accessed on 24 January 2020)]; Available online: https://clsi.org/

Alastruey-Izquierdo A., Melhem M., Bonfietti L.X., Rodriguez-Tudela J.L. Susceptibility test for fungi: Clinical and laboratorial correlations in medical mycology. Rev. Inst. Med. Trop. São Paulo. 2015;57:57–64. doi: 10.1590/S0036-46652015000700011. PubMed DOI PMC

New Definitions of S, I and R from 2019. [(accessed on 23 January 2020)]; Available online: http://www.eucast.org/newsiandr/

Kahlmeter G., Giske C.G., Kirn T.J., Sharp S.E. Point-Counterpoint: Differences between the European Committee on Antimicrobial Susceptibility Testing and Clinical and Laboratory Standards Institute Recommendations for Reporting Antimicrobial Susceptibility Results. J. Clin. Microbiol. 2019;57:e01129-19. doi: 10.1128/JCM.01129-19. PubMed DOI PMC

Sanguinetti M., Posteraro B. Susceptibility Testing of Fungi to Antifungal Drugs. J. Fungi. 2018;4:110. doi: 10.3390/jof4030110. PubMed DOI PMC

Breakpoint Tables for Interpretation of MICs for Antifungal Agents, Version 10.0. [(accessed on 28 February 2020)]; Available online: http://www.eucast.org/astoffungi/clinicalbreakpointsforantifungals/

Tortorano A.M., Rautemaa-Richardson R., Roilides E., Van Diepeningen A., Caira M., Muñoz P., Johnson E., Meletiadis J., Pana Z.-D., Lackner M., et al. ESCMID and ECMM joint guidelines on diagnosis and management of hyalohyphomycosis: Fusarium spp., Scedosporium spp. and others. Clin. Microbiol. Infect. 2014;20:27–46. doi: 10.1111/1469-0691.12465. PubMed DOI

Sanguinetti M., Posteraro B., Lass-Flörl C. Antifungal drug resistance amongCandidaspecies: Mechanisms and clinical impact. Mycoses. 2015;58:2–13. doi: 10.1111/myc.12330. PubMed DOI

Morio F., Jensen R.H., Le Pape P., Arendrup M.C. Molecular basis of antifungal drug resistance in yeasts. Int. J. Antimicrob. Agents. 2017;50:599–606. doi: 10.1016/j.ijantimicag.2017.05.012. PubMed DOI

Beardsley J., Halliday C.L., Chen S.C.-A., Sorrell T. Responding to the emergence of antifungal drug resistance: Perspectives from the bench and the bedside. Futur. Microbiol. 2018;13:1175–1191. doi: 10.2217/fmb-2018-0059. PubMed DOI PMC

Verweij P.E., Chowdhary A., Melchers W.J.G., Meis J.F. Azole Resistance in Aspergillus fumigatus: Can We Retain the Clinical Use of Mold-Active Antifungal Azoles? Clin. Infect. Dis. 2015;62:362–368. doi: 10.1093/cid/civ885. PubMed DOI PMC

Berger S., El Chazli Y., Babu A.F., Coste A. Azole Resistance in Aspergillus fumigatus: A Consequence of Antifungal Use in Agriculture? Front. Microbiol. 2017;8:1024–1030. doi: 10.3389/fmicb.2017.01024. PubMed DOI PMC

Cutler J.E., Corti M., Lambert P., Ferris M., Xin H. Horizontal Transmission of Candida albicans and Evidence of a Vaccine Response in Mice Colonized with the Fungus. PLoS ONE. 2011;6:22030. doi: 10.1371/journal.pone.0022030. PubMed DOI PMC

Bliss J.M., Basavegowda K.P., Watson W.J., Sheikh A.U., Ryan R.M. Vertical and Horizontal Transmission of Candida albicans in Very Low Birth Weight Infants Using DNA Fingerprinting Techniques. Pediatr. Infect. Dis. J. 2008;27:231–235. doi: 10.1097/INF.0b013e31815bb69d. PubMed DOI

White T.C., Marr K.A., Bowden R.A. Clinical, Cellular, and Molecular Factors That Contribute to Antifungal Drug Resistance. Clin. Microbiol. Rev. 1998;11:382–402. doi: 10.1128/CMR.11.2.382. PubMed DOI PMC

Sanglard D. Emerging Threats in Antifungal-Resistant Fungal Pathogens. Front. Med. 2016;3:165. doi: 10.3389/fmed.2016.00011. PubMed DOI PMC

Bhattacharya S., Esquivel B.D., White T.C. Overexpression or Deletion of Ergosterol Biosynthesis Genes Alters Doubling Time, Response to Stress Agents, and Drug Susceptibility inSaccharomyces cerevisiae. mBio. 2018;9:e01291-18. doi: 10.1128/mBio.01291-18. PubMed DOI PMC

Hull C.M., Bader O., Parker J., Weig M., Gross U., Warrilow A., Kelly D.E., Kelly S.L. Two Clinical Isolates of Candida glabrata Exhibiting Reduced Sensitivity to Amphotericin B Both Harbor Mutations in ERG2. Antimicrob. Agents Chemother. 2012;56:6417–6421. doi: 10.1128/AAC.01145-12. PubMed DOI PMC

Mesa-Arango A.C., Rueda C., Román E., Quintin J., Terrón M.C., Luque D., Netea M.G., Pla J., Zaragoza O. Cell Wall Changes in Amphotericin B-Resistant Strains from Candida tropicalis and Relationship with the Immune Responses Elicited by the Host. Antimicrob. Agents Chemother. 2016;60:2326–2335. doi: 10.1128/AAC.02681-15. PubMed DOI PMC

Posch W., Blatzer M., Wilflingseder D., Lass-Floerl C. Aspergillus terreus: Novel lessons learned on amphotericin B resistance. Med. Mycol. 2018;56:S73–S82. doi: 10.1093/mmy/myx119. PubMed DOI

Costa C., Ponte A., Pais P., Santos R., Cavalheiro M., Yaguchi T., Chibana H., Teixeira M.C. New Mechanisms of Flucytosine Resistance in C. glabrata Unveiled by a Chemogenomics Analysis in S. cerevisiae. PLoS ONE. 2015;10:e0135110. doi: 10.1371/journal.pone.0135110. PubMed DOI PMC

Gsaller F., Furukawa T., Carr P.D., Rash B., Jöchl C., Bertuzzi M., Bignell E., Bromley M.J. Mechanistic Basis of pH-Dependent 5-Flucytosine Resistance inAspergillus fumigatus. Antimicrob. Agents Chemother. 2018;62:e02593-17. doi: 10.1128/AAC.02593-17. PubMed DOI PMC

Cowen L., Sanglard D., Howard S.J., Rogers P.D., Perlin D. Mechanisms of Antifungal Drug Resistance. Cold Spring Harb. Perspect. Med. 2014;5:a019752. doi: 10.1101/cshperspect.a019752. PubMed DOI PMC

Rodrigues C.F., Rodrigues M.E., Henriques M. Susceptibility of Candida glabrata biofilms to echinocandins: Alterations in the matrix composition. Biofouling. 2018;34:569–578. doi: 10.1080/08927014.2018.1472244. PubMed DOI

Perlin D. Echinocandin Resistance in Candida. Clin. Infect. Dis. 2015;61:S612–S617. doi: 10.1093/cid/civ791. PubMed DOI PMC

Al-Hatmi A.M.S., Normand A.-C., Ranque S., Piarroux R., De Hoog G.S., Meletiadis J., Meis J.F. Comparative Evaluation of Etest, EUCAST, and CLSI Methods for Amphotericin B, Voriconazole, and Posaconazole against Clinically Relevant Fusarium Species. Antimicrob. Agents Chemother. 2016;61:e01671-16. doi: 10.1128/AAC.01671-16. PubMed DOI PMC

Al-Hatmi A.M., Meis J.F., De Hoog G.S. Fusarium: Molecular Diversity and Intrinsic Drug Resistance. PLOS Pathog. 2016;12:e1005464. doi: 10.1371/journal.ppat.1005464. PubMed DOI PMC

Johnson M.E., Katiyar S.K., Edlind T.D. New Fks Hot Spot for Acquired Echinocandin Resistance in Saccharomyces cerevisiae and Its Contribution to Intrinsic Resistance of Scedosporium Species. Antimicrob. Agents Chemother. 2011;55:3774–3781. doi: 10.1128/AAC.01811-10. PubMed DOI PMC

Caramalho R., Tyndall J.D.A., Monk B.C., Larentis T., Lass-Flörl C., Lackner M. Intrinsic short-tailed azole resistance in mucormycetes is due to an evolutionary conserved aminoacid substitution of the lanosterol 14α-demethylase. Sci. Rep. 2017;7:15898. doi: 10.1038/s41598-017-16123-9. PubMed DOI PMC

Schell W.A., Jones A.M., Garvey E.P., Hoekstra W.J., Schotzinger R.J., Alexander B.D. Fungal CYP51 Inhibitors VT-1161 and VT-1129 Exhibit Strong In Vitro Activity against Candida glabrata and C. krusei Isolates Clinically Resistant to Azole and Echinocandin Antifungal Compounds. Antimicrob. Agents Chemother. 2017;61:e01817-16. doi: 10.1128/AAC.01817-16. PubMed DOI PMC

Database of Privately and Publicly Funded Clinical Studies. [(accessed on 2 March 2020)]; Available online: https://clinicaltrials.gov/ct2/home.

VT-1161 and VT-1598 Pipeline. [(accessed on 2 March 2020)]; Available online: https://www.mycovia.com/pipeline.

Colley T., Sharma C., Alanio A., Kimura G., Daly L., Nakaoki T., Nishimoto Y., Bretagne S., Kizawa Y., Strong P., et al. Anti-fungal activity of a novel triazole, PC1244, against emerging azole-resistant Aspergillus fumigatus and other species of Aspergillus. J. Antimicrob. Chemother. 2019;74:2950–2958. doi: 10.1093/jac/dkz302. PubMed DOI PMC

Rauseo A.M., Coler-Reilly A., Larson L., Spec A. Hope on the Horizon: Novel Fungal Treatments in Development. Open Forum Infect. Dis. 2020;7:1–19. doi: 10.1093/ofid/ofaa016. PubMed DOI PMC

Wiederhold N.P. The antifungal arsenal: Alternative drugs and future targets. Int. J. Antimicrob. Agents. 2017;51:333–339. doi: 10.1016/j.ijantimicag.2017.09.002. PubMed DOI

Gintjee T.J., Donnelley M.A., Thompson G.R. Aspiring Antifungals: Review of Current Antifungal Pipeline Developments. J. Fungi. 2020;6:28. doi: 10.3390/jof6010028. PubMed DOI PMC

Nicola A.M., Albuquerque P., Paes H.C., Fernandes L., Costa F.F., Kioshima E.S., Abadio A.K.R., Bocca A.L., Felipe M.S. Antifungal drugs: New insights in research & development. Pharmacol. Ther. 2019;195:21–38. PubMed

Perfect J.R. The antifungal pipeline: A reality check. Nat. Rev. Drug Discov. 2017;16:603–616. doi: 10.1038/nrd.2017.46. PubMed DOI PMC

Alkhazraji S., Gebremariam T., Alqarihi A., Gu Y., Mamouei Z., Singh S., Wiederhold N.P., Shaw K.J., Ibrahim A.S. Fosmanogepix (APX001) Is Effective in the Treatment of Immunocompromised Mice Infected with Invasive Pulmonary Scedosporiosis or Disseminated Fusariosis. Antimicrob. Agents Chemother. 2020;64:1–12. doi: 10.1128/AAC.01735-19. PubMed DOI PMC

Van Daele R., Spriet I., Wauters J., Maertens J., Mercier T., Van Hecke S., Brüggemann R. Antifungal drugs: What brings the future? Med. Mycol. 2019;57:S328–S343. doi: 10.1093/mmy/myz012. PubMed DOI

Su H., Han L., Huang X. Potential targets for the development of new antifungal drugs. J. Antibiot. 2018;71:978–991. doi: 10.1038/s41429-018-0100-9. PubMed DOI

Haranahalli K., Lazzarini C., Sun Y., Zambito J., Pathiranage S., McCarthy J.B., Mallamo J.P., Del Poeta M., Ojima I. SAR Studies on Aromatic Acylhydrazone-Based Inhibitors of Fungal Sphingolipid Synthesis as Next-Generation Antifungal Agents. J. Med. Chem. 2019;62:8249–8273. doi: 10.1021/acs.jmedchem.9b01004. PubMed DOI PMC

Lazzarini C., Haranahalli K., Rieger R., Ananthula H.K., Desai P.B., Ashbaugh A., Linke M.J., Cushion M.T., Ruzsicska B., Haley J., et al. Acylhydrazones as Antifungal Agents Targeting the Synthesis of Fungal Sphingolipids. Antimicrob. Agents Chemother. 2018;62:e00156-18. doi: 10.1128/AAC.00156-18. PubMed DOI PMC

Ribeiro M., Simões M. Advances in the antimicrobial and therapeutic potential of siderophores. Environ. Chem. Lett. 2019;17:1485–1494. doi: 10.1007/s10311-019-00887-9. DOI

Lamb A.L. Breaking a pathogen’s iron will: Inhibiting siderophore production as an antimicrobial strategy. Biochim. Biophys. Acta Proteins Proteom. 2015;1854:1054–1070. doi: 10.1016/j.bbapap.2015.05.001. PubMed DOI PMC

Del Campo J.S.M., Vogelaar N., Tolani K., Kizjakina K., Harich K., Sobrado P. Inhibition of the Flavin-Dependent Monooxygenase Siderophore A (SidA) Blocks Siderophore Biosynthesis and Aspergillus fumigatus Growth. ACS Chem. Boil. 2016;11:3035–3042. doi: 10.1021/acschembio.6b00666. PubMed DOI

Leblanc C., Prudhomme T., Tabouret G., Ray A., Burbaud S., Cabantous S., Mourey L., Guilhot C., Chalut C. 4′-Phosphopantetheinyl Transferase PptT, a New Drug Target Required for Mycobacterium tuberculosis Growth and Persistence In Vivo. PLOS Pathog. 2012;8:e1003097. doi: 10.1371/journal.ppat.1003097. PubMed DOI PMC

Foley T.L., Young B.S., Burkart M.D. Phosphopantetheinyl transferase inhibition and secondary metabolism. FEBS J. 2009;276:7134–7145. doi: 10.1111/j.1742-4658.2009.07425.x. PubMed DOI

Golonka R., Vijay-Kumar M., Vijay-Kumar M. The Iron Tug-of-War between Bacterial Siderophores and Innate Immunity. J. Innate Immun. 2019;11:249–262. doi: 10.1159/000494627. PubMed DOI PMC

Mammen M.P., Armas D., Hughes F.H., Hopkins A.M., Fisher C.L., Resch P.A., Rusalov D., Sullivan S.M., Smith L.R. First-in-Human Phase 1 Study To Assess Safety, Tolerability, and Pharmacokinetics of a Novel Antifungal Drug, VL-2397, in Healthy Adults. Antimicrob. Agents Chemother. 2019;63:1–41. doi: 10.1128/AAC.00969-19. PubMed DOI PMC

Petrik M., Zhai C., Haas H., Decristoforo C. Siderophores for molecular imaging applications. Clin. Transl. Imaging. 2016;5:15–27. doi: 10.1007/s40336-016-0211-x. PubMed DOI PMC

Luptáková D., Pluháček T., Petrik M., Novak J., Palyzová A., Sokolová L., Škríba A., Šedivá B., Lemr K., Havlicek V. Non-invasive and invasive diagnoses of aspergillosis in a rat model by mass spectrometry. Sci. Rep. 2017;7:16523. doi: 10.1038/s41598-017-16648-z. PubMed DOI PMC

Beyond Conventional Antifungals: Combating Resistance Through Novel Therapeutic Pathways

Freeing Aspergillus fumigatus of Polymycovirus Infection Renders It More Resistant to Competition with Pseudomonas aeruginosa Due to Altered Iron-Acquiring Tactics

Rhizoferrin Glycosylation in Rhizopus microsporus