Review

Department of Oral Biology, University of Florida College of Dentistry, Gainesville, FL 32610, USA

Search for more papers by this author

Luis R Martinez

*Author for correspondence:

E-mail Address: lmartinez@dental.ufl.edu

https://orcid.org/0000-0001-6372-6501

Department of Oral Biology, University of Florida College of Dentistry, Gainesville, FL 32610, USA

Emerging Pathogens Institute, University of Florida, Gainesville, FL 32610, USA

Center for Immunology and Transplantation, University of Florida, Gainesville, FL 32610, USA

Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL 32610, USA

Search for more papers by this author

Published Online:26 Sep 2023https://doi.org/10.2217/fmb-2022-0269

View article

Abstract

Fungal infections are a serious problem affecting many people worldwide, creating critical economic and medical consequences. Fungi are ubiquitous and can cause invasive diseases in individuals mostly living in developing countries or with weakened immune systems, and antifungal drugs currently available have important limitations in tolerability and efficacy. In an effort to counteract the high morbidity and mortality rates associated with invasive fungal infections, various approaches are being utilized to discover and develop new antifungal agents. This review discusses the challenges posed by fungal infections, outlines different methods for developing antifungal drugs and reports on the status of drugs currently in clinical trials, which offer hope for combating this serious global problem.

Keywords:

Papers of special note have been highlighted as: • of interest; •• of considerable interest

References

1. Carmona EM, Limper AH. Overview of treatment approaches for fungal infections. Clin. Chest Med. 38(3), 393–402 (2017).
MedlineGoogle Scholar
2. Brown GD, Denning DW, Gow NA, Levitz SM, Netea MG, White TC. Hidden killers: human fungal infections. Sci. Transl. Med. 4(165), 165rv113 (2012).
Google Scholar
3. WHO. WHO releases first-ever list of health-threatening fungi (2022). www.who.int/news/item/25-10-2022-who-releases-first-ever-list-of-health-threatening-fungi (Accessed 2 December 2022).
Google Scholar
4. Fisher MC, Henk DA, Briggs CJ et al. Emerging fungal threats to animal, plant and ecosystem health. Nature 484(7393), 186–194 (2012).
Medline CASGoogle Scholar
5. Revie NM, Iyer KR, Robbins N, Cowen LE. Antifungal drug resistance: evolution, mechanisms and impact. Curr. Opin. Microbiol. 45, 70–76 (2018).
Medline CASGoogle Scholar
6. Fisher MC, Hawkins NJ, Sanglard D, Gurr SJ. Worldwide emergence of resistance to antifungal drugs challenges human health and food security. Science 360(6390), 739–742 (2018).
Medline CASGoogle Scholar
7. Low CY, Rotstein C. Emerging fungal infections in immunocompromised patients. F1000 Med. Rep. 3, 14 (2011).
MedlineGoogle Scholar
8. Gonzalez-Lara MF, Sifuentes-Osornio J, Ostrosky-Zeichner L. Drugs in clinical development for fungal infections. Drugs 77(14), 1505–1518 (2017).
Medline CASGoogle Scholar
9. McKeny PT, Trevor NA, Zito PM. Antifungal antibiotics. In: StatPearls. StatPearls Publishing, Treasure Island, FL, USA (2022). https://www.ncbi.nih.gov/books/NBK538168/
Google Scholar
10. Rauseo AM, Coler-Reilly A, Larson L, Spec A. Hope on the horizon: novel fungal treatments in development. Open Forum Infect. Dis. 7(2), ofaa016 (2020).
Medline CASGoogle Scholar
11. Casadevall A, Kontoyiannis DP, Robert V. On the emergence of Candida auris: climate change, azoles, swamps, and birds. mBio 10(4), e01397 (2019).
MedlineGoogle Scholar
12. Casadevall A, Kontoyiannis DP, Robert V. Environmental Candida auris and the global warming emergence hypothesis. mBio 12(2), e00360 (2021).
MedlineGoogle Scholar
13. Singh S, Chandra U, Anchan VN, Verma P, Tilak R. Limited effectiveness of four oral antifungal drugs (fluconazole, griseofulvin, itraconazole and terbinafine) in the current epidemic of altered dermatophytosis in India: results of a randomized pragmatic trial. Br. J. Dermatol. 183(5), 840–846 (2020).
Medline CASGoogle Scholar
14. The American Association of Neurological Surgeons ASoNC, Interventional Radiology Society of Europe CIRACoNSESoMINTESoNESOSfCA, Interventions SoIRSoNS et al. Multisociety consensus quality improvement revised consensus statement for endovascular therapy of acute ischemic stroke. Int. J. Stroke 13(6), 612–632 (2018).
MedlineGoogle Scholar
15. Mukherjee PK, Sheehan DJ, Hitchcock CA, Ghannoum MA. Combination treatment of invasive fungal infections. Clin. Microbiol. Rev. 18(1), 163–194 (2005). • Describes the issues with current antifungal treatment while providing a comprehensive discussion of the impact of combination treatment. Standardization testing and analysis of combination therapy will allow for advancement in drug development.
Medline CASGoogle Scholar
16. Srinivasan A, Lopez-Ribot JL, Ramasubramanian AK. Overcoming antifungal resistance. Drug Discov. Today Technol. 11, 65–71 (2014). •• Discusses the challenges in developing new anti fungal agent and highlight the importance of combination therapies, drug repurposing and alternative therapies. Discusses the potential role of novel drug-delivery system in improving drug efficacy and rehung drug resistance.
MedlineGoogle Scholar
17. Wall G, Lopez-Ribot JL. Current antimycotics, new prospects, and future approaches to antifungal therapy. Antibiotics (Basel) 9(8), 445 (2020).
Medline CASGoogle Scholar
18. Johnson PC, Wheat LJ, Cloud GA et al. Safety and efficacy of liposomal amphotericin B compared with conventional amphotericin B for induction therapy of histoplasmosis in patients with AIDS. Ann. Intern. Med. 137(2), 105–109 (2002).
Medline CASGoogle Scholar
19. Bennett JE, Dismukes WE, Duma RJ et al. A comparison of amphotericin B alone and combined with flucytosine in the treatment of cryptoccal meningitis. N. Engl. J. Med. 301(3), 126–131 (1979).
Medline CASGoogle Scholar
20. Vermes A, Guchelaar HJ, Dankert J. Flucytosine: a review of its pharmacology, clinical indications, pharmacokinetics, toxicity and drug interactions. J. Antimicrob. Chemother. 46(2), 171–179 (2000).
Medline CASGoogle Scholar
21. Loyse A, Thangaraj H, Easterbrook P et al. Cryptococcal meningitis: improving access to essential antifungal medicines in resource-poor countries. Lancet Infect. Dis. 13(7), 629–637 (2013).
MedlineGoogle Scholar
22. Kneale M, Bartholomew JS, Davies E, Denning DW. Global access to antifungal therapy and its variable cost. J. Antimicrob. Chemother. 71(12), 3599–3606 (2016).
Medline CASGoogle Scholar
23. Bicanic T, Wood R, Bekker LG, Darder M, Meintjes G, Harrison TS. Antiretroviral roll-out, antifungal roll-back: access to treatment for cryptococcal meningitis. Lancet Infect. Dis. 5(9), 530–531 (2005).
MedlineGoogle Scholar
24. Daum G, Lees ND, Bard M, Dickson R. Biochemistry, cell biology and molecular biology of lipids of Saccharomyces cerevisiae. Yeast 14(16), 1471–1510 (1998).
Medline CASGoogle Scholar
25. Marks DI, Pagliuca A, Kibbler CC et al. Voriconazole versus itraconazole for antifungal prophylaxis following allogeneic haematopoietic stem-cell transplantation. Br. J. Haematol. 155(3), 318–327 (2011).
Medline CASGoogle Scholar
26. Birnbaum JE. Pharmacology of the allylamines. J. Am. Acad. Dermatol. 23(4 Pt 2), 782–785 (1990).
Medline CASGoogle Scholar
27. Demuyser L, Van Dyck K, Timmermans B, Van Dijck P. Inhibition of vesicular transport influences fungal susceptibility to fluconazole. Antimicrob. Agents Chemother. 63(5), e01998 (2018).
Google Scholar
28. Ghannoum MA, Rice LB. Antifungal agents: mode of action, mechanisms of resistance, and correlation of these mechanisms with bacterial resistance. Clin. Microbiol. Rev. 12(4), 501–517 (1999).
Medline CASGoogle Scholar
29. Pfaller MA, Boyken L, Hollis RJ, Messer SA, Tendolkar S, Diekema DJ. In vitro susceptibilities of clinical isolates of Candida species, Cryptococcus neoformans, and Aspergillus species to itraconazole: global survey of 9359 isolates tested by clinical and laboratory standards institute broth microdilution methods. J. Clin. Microbiol. 43(8), 3807–3810 (2005).
Medline CASGoogle Scholar
30. Yoshida I, Saito AM, Tanaka S et al. Intravenous itraconazole compared with liposomal amphotericin B as empirical antifungal therapy in patients with neutropaenia and persistent fever. Mycoses 63(8), 794–801 (2020).
Medline CASGoogle Scholar
31. Chaftari AM, Hachem RY, Ramos E et al. Comparison of posaconazole versus weekly amphotericin B lipid complex for the prevention of invasive fungal infections in hematopoietic stem-cell transplantation. Transplantation 94(3), 302–308 (2012).
Medline CASGoogle Scholar
32. Liu K, Wu D, Li J et al. Pharmacokinetics and safety of posaconazole tablet formulation in Chinese participants at high risk for invasive fungal infection. Adv. Ther. 37(5), 2493–2506 (2020).
Medline CASGoogle Scholar
33. Sun QN, Fothergill AW, McCarthy DI, Rinaldi MG, Graybill JR. In vitro activities of posaconazole, itraconazole, voriconazole, amphotericin B, and fluconazole against 37 clinical isolates of zygomycetes. Antimicrob. Agents Chemother. 46(5), 1581–1582 (2002).
Medline CASGoogle Scholar
34. Pfaller MA, Messer SA, Hollis RJ, Jones RN, Group SP. Antifungal activities of posaconazole, ravuconazole, and voriconazole compared to those of itraconazole and amphotericin B against 239 clinical isolates of Aspergillus spp. and other filamentous fungi: report from SENTRY Antimicrobial Surveillance Program, 2000. Antimicrob. Agents Chemother. 46(4), 1032–1037 (2002).
Medline CASGoogle Scholar
35. Sabatelli F, Patel R, Mann PA et al. In vitro activities of posaconazole, fluconazole, itraconazole, voriconazole, and amphotericin B against a large collection of clinically important molds and yeasts. Antimicrob. Agents Chemother. 50(6), 2009–2015 (2006).
Medline CASGoogle Scholar
36. Kersemaekers WM, van Iersel T, Nassander U et al. Pharmacokinetics and safety study of posaconazole intravenous solution administered peripherally to healthy subjects. Antimicrob. Agents Chemother. 59(2), 1246–1251 (2015).
MedlineGoogle Scholar
37. Sime FB, Stuart J, Butler J et al. Pharmacokinetics of intravenous posaconazole in critically ill patients with hypoalbuminaemia receiving continuous venovenous haemodiafiltration. Antimicrob. Agents Chemother. 62(6), 506–509 (2018).
Google Scholar
38. Marks DI, Liu Q, Slavin M. Voriconazole for prophylaxis of invasive fungal infections after allogeneic hematopoietic stem cell transplantation. Expert Rev. Anti Infect. Ther. 15(5), 493–502 (2017).
Medline CASGoogle Scholar
39. Hendrix MJ, Larson L, Rauseo AM et al. Voriconazole versus itraconazole for the initial and step-down treatment of histoplasmosis: a retrospective cohort. Clin. Infect. Dis. 73(11), e3727–e3732 (2021).
Medline CASGoogle Scholar
40. Park WB, Kim NH, Kim KH et al. The effect of therapeutic drug monitoring on safety and efficacy of voriconazole in invasive fungal infections: a randomized controlled trial. Clin. Infect. Dis. 55(8), 1080–1087 (2012).
Medline CASGoogle Scholar
41. Chen SC, Slavin MA, Sorrell TC. Echinocandin antifungal drugs in fungal infections: a comparison. Drugs 71(1), 11–41 (2011).
MedlineGoogle Scholar
42. Aguilar-Zapata D, Petraitiene R, Petraitis V. Echinocandins: the expanding antifungal armamentarium. Clin. Infect. Dis. 61(Suppl. 6), S604–S611 (2015).
Medline CASGoogle Scholar
43. Glasmacher A, Cornely OA, Orlopp K et al. Caspofungin treatment in severely ill, immunocompromised patients: a case-documentation study of 118 patients. J. Antimicrob. Chemother. 57(1), 127–134 (2006).
Medline CASGoogle Scholar
44. Muilwijk EW, Schouten JA, van Leeuwen HJ et al. Pharmacokinetics of caspofungin in ICU patients. J. Antimicrob. Chemother. 69(12), 3294–3299 (2014).
Medline CASGoogle Scholar
45. Kim J, Nakwa FL, Araujo Motta F et al. A randomized, double-blind trial investigating the efficacy of caspofungin versus amphotericin B deoxycholate in the treatment of invasive candidiasis in neonates and infants younger than 3 months of age. J. Antimicrob. Chemother. 75(1), 215–220 (2020).
Medline CASGoogle Scholar
46. Kontoyiannis DP, Bassetti M, Nucci M et al. Anidulafungin for the treatment of candidaemia caused by Candida parapsilosis: analysis of pooled data from six prospective clinical studies. Mycoses 60(10), 663–667 (2017).
Medline CASGoogle Scholar
47. van der Geest PJ, Hunfeld NG, Ladage SE, Groeneveld AB. Micafungin versus anidulafungin in critically ill patients with invasive candidiasis: a retrospective study. BMC Infect. Dis. 16, 490 (2016).
MedlineGoogle Scholar
48. van Burik JA, Ratanatharathorn V, Stepan DE et al. Micafungin versus fluconazole for prophylaxis against invasive fungal infections during neutropenia in patients undergoing hematopoietic stem cell transplantation. Clin. Infect. Dis. 39(10), 1407–1416 (2004).
Medline CASGoogle Scholar
49. Jeong SH, Kim DY, Jang JH et al. Efficacy and safety of micafungin versus intravenous itraconazole as empirical antifungal therapy for febrile neutropenic patients with hematological malignancies: a randomized, controlled, prospective, multicenter study. Ann. Hematol. 95(2), 337–344 (2016).
Medline CASGoogle Scholar
50. McCarty TP, Lockhart SR, Moser SA et al. Echinocandin resistance among Candida isolates at an academic medical centre 2005-15: analysis of trends and outcomes. J. Antimicrob. Chemother. 73(6), 1677–1680 (2018).
Medline CASGoogle Scholar
51. Caplan T, Lorente-Macias A, Stogios PJ et al. Overcoming fungal echinocandin resistance through inhibition of the non-essential stress kinase Yck2. Cell Chem. Biol. 27(3), 269–282.e5 (2020).
Medline CASGoogle Scholar
52. Cao C, Wang Y, Husain S, Soteropoulos P, Xue C. A mechanosensitive channel governs lipid flippase-mediated echinocandin resistance in Cryptococcus neoformans. mBio 10(6), e01952 (2019).
Medline CASGoogle Scholar
53. Vago T, Baldi G, Colombo D et al. Effects of naftifine and terbinafine, two allylamine antifungal drugs, on selected functions of human polymorphonuclear leukocytes. Antimicrob. Agents Chemother. 38(11), 2605–2611 (1994).
Medline CASGoogle Scholar
54. Loyse A, Dromer F, Day J, Lortholary O, Harrison TS. Flucytosine and cryptococcosis: time to urgently address the worldwide accessibility of a 50-year-old antifungal. J. Antimicrob. Chemother. 68(11), 2435–2444 (2013).
Medline CASGoogle Scholar
55. Robbins N, Wright GD, Cowen LE. Antifungal drugs: the current armamentarium and development of new agents. Microbiol. Spectr. 4(5), FUNK-0002 (2016). •• Discusses the mechanisms of action and limitations of current antifungals and highlight identifying new targets, repurposing existing drugs and using novel drug-delivery systems. Emphasized the need for continued research and development of new anti fungal agents to combat antifungal resistance.
Google Scholar
56. Hospenthal DR, Bennett JE. Flucytosine monotherapy for cryptococcosis. Clin. Infect. Dis. 27(2), 260–264 (1998).
Medline CASGoogle Scholar
57. Zhao T, Xu X, Wu Y et al. Comparison of amphotericin B deoxycholate in combination with either flucytosine or fluconazole, and voriconazole plus flucytosine for the treatment of HIV-associated cryptococcal meningitis: a prospective multicenter study in China. BMC Infect. Dis. 22(1), 677 (2022).
Medline CASGoogle Scholar
58. Wu W, Lan W, Wu C, Fei Q. Synthesis and antifungal activity of pyrimidine derivatives containing an amide moiety. Front. Chem. 9, 695628 (2021).
Medline CASGoogle Scholar
59. CDC. Antimicrobial-resistant fungi (2022). www.cdc.gov/fungal/antifungal-resistance.html (Accessed 1 December 2022).
Google Scholar
60. Rosenberg A, Ene IV, Bibi M et al. Antifungal tolerance is a subpopulation effect distinct from resistance and is associated with persistent candidemia. Nat. Commun. 9(1), 2470 (2018).
MedlineGoogle Scholar
61. Berman J, Krysan DJ. Drug resistance and tolerance in fungi. Nat. Rev. Microbiol. 18(6), 319–331 (2020).
Medline CASGoogle Scholar
62. Teng X, Wang Y, Gu J, Shi P, Shen Z, Ye L. Antifungal agents: design, synthesis, antifungal activity and molecular docking of phloroglucinol derivatives. Molecules 23(12), 3116 (2018).
MedlineGoogle Scholar
63. Bhattacharya S, Sae-Tia S, Fries BC. Candidiasis and mechanisms of antifungal resistance. Antibiotics (Basel) 9(6), 312 (2020).
Medline CASGoogle Scholar
64. Perlin DS. Mechanisms of echinocandin antifungal drug resistance. Ann. NY Acad. Sci. 1354(1), 1–11 (2015).
Medline CASGoogle Scholar
65. Al-Baqsami ZF, Ahmad S, Khan Z. Antifungal drug susceptibility, molecular basis of resistance to echinocandins and molecular epidemiology of fluconazole resistance among clinical Candida glabrata isolates in Kuwait. Sci. Rep. 10(1), 6238 (2020).
Medline CASGoogle Scholar
66. McCarthy M, O'Shaughnessy EM, Walsh TJ. Amphotericin B: polyene resistance mechanisms. In: Antimicrobial Drug Resistance: Mechanisms of Drug Resistance, Volume 1. Mayers DLSobel JDOuellette MKaye KSMarchaim D (Eds). Springer International Publishing, Cham, Switzerland, 387–395 (2017).
Google Scholar
67. Lagowski D, Gnat S, Nowakiewicz A, Osinska M, Dylag M. Intrinsic resistance to terbinafine among human and animal isolates of Trichophyton mentagrophytes related to amino acid substitution in the squalene epoxidase. Infection 48(6), 889–897 (2020).
Medline CASGoogle Scholar
68. Bermas A, Geddes-McAlister J. Combatting the evolution of antifungal resistance in Cryptococcus neoformans. Mol. Microbiol. 114(5), 721–734 (2020).
Medline CASGoogle Scholar
69. Lewis RE. Current concepts in antifungal pharmacology. Mayo Clin. Proc. 86(8), 805–817 (2011).
Medline CASGoogle Scholar
70. Andes D, Pascual A, Marchetti O. Antifungal therapeutic drug monitoring: established and emerging indications. Antimicrob. Agents Chemother. 53(1), 24–34 (2009).
Medline CASGoogle Scholar
71. Abdel-Hafez Y, Siaj H, Janajri M et al. Tolerability and epidemiology of nephrotoxicity associated with conventional amphotericin B therapy: a retrospective study in tertiary care centers in Palestine. BMC Nephrol. 23(1), 132 (2022).
MedlineGoogle Scholar
72. Shoham S, Groll AH, Petraitis V, Walsh TJ. Systemic antifungal agents. In: Infectious Diseases (4th Edition). Cohen JPowderly WGOpal SM (Eds). Elsevier, Amsterdam, Netherlands. 1333–1344; e4 (2017).
Google Scholar
73. Walsh TJ, Finberg RW, Arndt C et al. Liposomal amphotericin B for empirical therapy in patients with persistent fever and neutropenia. National Institute of Allergy and Infectious Diseases Mycoses Study Group. N. Engl. J. Med. 340(10), 764–771 (1999).
Medline CASGoogle Scholar
74. Tverdek FP, Kofteridis D, Kontoyiannis DP. Antifungal agents and liver toxicity: a complex interaction. Expert Rev. Anti Infect. Ther. 14(8), 765–776 (2016).
Medline CASGoogle Scholar
75. Nivoix Y, Ledoux MP, Herbrecht R. Antifungal therapy: new and evolving therapies. Semin. Respir. Crit. Care Med. 41(1), 158–174 (2020).
MedlineGoogle Scholar
76. Mourad A, Perfect JR. Tolerability profile of the current antifungal armoury. J. Antimicrob. Chemother. 73(Suppl. 1), i26–i32 (2018).
Medline CASGoogle Scholar
77. Alsowaida YS PB, Almulhim AS, Kalbasi A. 1159. Echinocandins dosing in obese patients: a systematic review. Open Forum Infect. Dis. 7(Suppl. 1), S606 (2020).
Google Scholar
78. Kauffman CA, Frame PT. Bone marrow toxicity associated with 5-fluorocytosine therapy. Antimicrob. Agents Chemother. 11(2), 244–247 (1977).
Medline CASGoogle Scholar
79. Barnette DA, Davis MA, Dang NL et al. Lamisil (terbinafine) toxicity: determining pathways to bioactivation through computational and experimental approaches. Biochem. Pharmacol. 156, 10–21 (2018).
Medline CASGoogle Scholar
80. Bicanic T, Bottomley C, Loyse A et al. Toxicity of amphotericin B deoxycholate-based induction therapy in patients with HIV-associated cryptococcal meningitis. Antimicrob. Agents Chemother. 59(12), 7224–7231 (2015).
Medline CASGoogle Scholar
81. Bodey GP, Anaissie EJ, Elting LS, Estey E, O'Brien S, Kantarjian H. Antifungal prophylaxis during remission induction therapy for acute leukemia fluconazole versus intravenous amphotericin B. Cancer 73(8), 2099–2106 (1994).
Medline CASGoogle Scholar
82. Boonstra JM, van der Elst KC, Veringa A et al. Pharmacokinetic properties of micafungin in critically ill patients diagnosed with invasive candidiasis. Antimicrob. Agents Chemother. 61(12), e01398 (2017).
MedlineGoogle Scholar
83. Liu P, Mould DR. Population pharmacokinetic analysis of voriconazole and anidulafungin in adult patients with invasive aspergillosis. Antimicrob. Agents Chemother. 58(8), 4718–4726 (2014).
MedlineGoogle Scholar
84. Walsh TJ, Driscoll T, Milligan PA et al. Pharmacokinetics, safety, and tolerability of voriconazole in immunocompromised children. Antimicrob. Agents Chemother. 54(10), 4116–4123 (2010).
Medline CASGoogle Scholar
85. Smith KD, Achan B, Hullsiek KH et al. Increased antifungal drug resistance in clinical isolates of Cryptococcus neoformans in Uganda. Antimicrob. Agents Chemother. 59(12), 7197–7204 (2015).
Medline CASGoogle Scholar
86. Pace JR, DeBerardinis AM, Sail V et al. Repurposing the clinically efficacious antifungal agent itraconazole as an anticancer chemotherapeutic. J. Med. Chem. 59(8), 3635–3649 (2016).
Medline CASGoogle Scholar
87. Geronikaki A, Kartsev V, Petrou A et al. Antibacterial activity of griseofulvin analogues as an example of drug repurposing. Int. J. Antimicrob. Agents 55(3), 105884 (2020).
Medline CASGoogle Scholar
88. Zhang Q, Liu F, Zeng M, Mao Y, Song Z. Drug repurposing strategies in the development of potential antifungal agents. Appl. Microbiol. Biotechnol. 105(13), 5259–5279 (2021).
Medline CASGoogle Scholar
89. Thangamani S, Maland M, Mohammad H et al. Repurposing approach identifies auranofin with broad spectrum antifungal activity that targets Mia40–Erv1 pathway. Front. Cell. Infect. Microbiol. 7, 4 (2017).
MedlineGoogle Scholar
90. Koromina M, Pandi MT, Patrinos GP. Rethinking drug repositioning and development with artificial intelligence, machine learning, and omics. OMICS 23(11), 539–548 (2019).
Medline CASGoogle Scholar
91. Chakravarty K, Antontsev VG, Khotimchenko M et al. Accelerated repurposing and drug development of pulmonary hypertension therapies for COVID-19 treatment using an AI-integrated biosimulation platform. Molecules 26(7), 1912 (2021).
Medline CASGoogle Scholar
92. Challa AP, Lavieri RR, Lewis JT et al. Systematically prioritizing candidates in genome-based drug repurposing. Assay Drug Dev. Technol. 17(8), 352–363 (2019).
Medline CASGoogle Scholar
93. Labode J, Dullin C, Wagner WL, Myti D, Morty RE, Muhlfeld C. Evaluation of classifications of the monopodial bronchopulmonary vasculature using clustering methods. Histochem. Cell Biol. 158(5), 435–445 (2022).
Medline CASGoogle Scholar
94. Siles SA, Srinivasan A, Pierce CG, Lopez-Ribot JL, Ramasubramanian AK. High-throughput screening of a collection of known pharmacologically active small compounds for identification of Candida albicans biofilm inhibitors. Antimicrob. Agents Chemother. 57(8), 3681–3687 (2013).
Medline CASGoogle Scholar
95. Sun W, Park YD, Sugui JA et al. Rapid identification of antifungal compounds against Exserohilum rostratum using high throughput drug repurposing screens. PLoS ONE 8(8), e70506 (2013).
Medline CASGoogle Scholar
96. Ji C, Liu N, Tu J et al. Drug repurposing of haloperidol: discovery of new benzocyclane derivatives as potent antifungal agents against cryptococcosis and candidiasis. ACS Infect. Dis. 6(5), 768–786 (2020).
Medline CASGoogle Scholar
97. Yang W, Tu J, Ji C et al. Discovery of piperidol derivatives for combinational treatment of azole-resistant candidiasis. ACS Infect. Dis. 7(3), 650–660 (2021).
Medline CASGoogle Scholar
98. El-Ganiny AM, Kamel HA, Yossef NE, Mansour B, El-Baz AM. Repurposing pantoprazole and haloperidol as efflux pump inhibitors in azole resistant clinical Candida albicans and non-albicans isolates. Saudi Pharm. J. 30(3), 245–255 (2022).
Medline CASGoogle Scholar
99. Mangione W, Falls Z, Melendy T, Chopra G, Samudrala R. Shotgun drug repurposing biotechnology to tackle epidemics and pandemics. Drug Discov. Today 25(7), 1126–1128 (2020).
Medline CASGoogle Scholar
100. Li T, Li L, Du F et al. Activity and mechanism of action of antifungal peptides from microorganisms: a review. Molecules 26(11), 3438 (2021).
Medline CASGoogle Scholar
101. van Eijk M, Boerefijn S, Cen L et al. Cathelicidin-inspired antimicrobial peptides as novel antifungal compounds. Med. Mycol. 58(8), 1073–1084 (2020).
Medline CASGoogle Scholar
102. Martinez LR, Casadevall A. Cryptococcus neoformans cells in biofilms are less susceptible than planktonic cells to antimicrobial molecules produced by the innate immune system. Infect. Immun. 74(11), 6118–6123 (2006).
Medline CASGoogle Scholar
103. Ochiai A, Ogawa K, Fukuda M et al. Rice defensin OsAFP1 is a new drug candidate against human pathogenic fungi. Sci. Rep. 8(1), 11434 (2018).
MedlineGoogle Scholar
104. Kamli MR, Sabir JSM, Malik MA, Ahmad A. Human beta defensins-1, an antimicrobial peptide, kills Candida glabrata by generating oxidative stress and arresting the cell cycle in G0/G1 phase. Biomed. Pharmacother. 154, 113569 (2022).
Medline CASGoogle Scholar
105. Yoo YJ, Kwon I, Oh SR et al. Antifungal effects of synthetic human beta-defensin-3-C15 peptide on Candida albicans-infected root dentin. J. Endod. 43(11), 1857–1861 (2017).
MedlineGoogle Scholar
106. Herrera-Arellano A, Jimenez-Ferrer E, Vega-Pimentel AM et al. Clinical and mycological evaluation of therapeutic effectiveness of Solanum chrysotrichum standardized extract on patients with pityriasis capitis (dandruff). A double blind and randomized clinical trial controlled with ketoconazole. Planta Med. 70(6), 483–488 (2004).
Medline CASGoogle Scholar
107. da Silva AR, de Andrade Neto JB, da Silva CR et al. Berberine antifungal activity in fluconazole-resistant pathogenic yeasts: action mechanism evaluated by flow cytometry and biofilm growth inhibition in Candida spp. Antimicrob. Agents Chemother. 60(6), 3551–3557 (2016).
Medline CASGoogle Scholar
108. Kuhnert E, Li Y, Lan N et al. Enfumafungin synthase represents a novel lineage of fungal triterpene cyclases. Environ. Microbiol. 20(9), 3325–3342 (2018).
Medline CASGoogle Scholar
109. Schwebke JR, Sobel R, Gersten JK et al. Ibrexafungerp versus placebo for vulvovaginal candidiasis treatment: a phase 3, randomized, controlled superiority trial (VANISH 303). Clin. Infect. Dis. 74(11), 1979–1985 (2022).
Medline CASGoogle Scholar
110. Hoenigl M, Sprute R, Egger M et al. The antifungal pipeline: fosmanogepix, ibrexafungerp, olorofim, opelconazole, and rezafungin. Drugs 81(15), 1703–1729 (2021).
Medline CASGoogle Scholar
111. Nakamura I, Ohsumi K, Takeda S et al. ASP2397 is a novel natural compound that exhibits rapid and potent fungicidal activity against Aspergillus species through a specific transporter. Antimicrob. Agents Chemother. 63(10), 02689 (2018).
Google Scholar
112. Hassan N, Firdaus S, Padhi S, Ali A, Iqbal Z. Investigating natural antibiofilm components: a new therapeutic perspective against candidal vulvovaginitis. Med. Hypotheses 148, 110515 (2021).
Medline CASGoogle Scholar
113. Raad II, Zakhem AE, Helou GE, Jiang Y, Kontoyiannis DP, Hachem R. Clinical experience of the use of voriconazole, caspofungin or the combination in primary and salvage therapy of invasive aspergillosis in haematological malignancies. Int. J. Antimicrob. Agents 45(3), 283–288 (2015).
Medline CASGoogle Scholar
114. Petraitiene R, Petraitis V, Maung BW, Naing E, Kavaliauskas P, Walsh TJ. Posaconazole alone and in combination with caspofungin for treatment of experimental Exserohilum rostratum meningoencephalitis: developing new strategies for treatment of phaeohyphomycosis of the central nervous system. J. Fungi (Basel) 6(1), 33 (2020).
Medline CASGoogle Scholar
115. Tong Y, Zhang J, Wang L et al. Hyper-synergistic antifungal activity of rapamycin and peptide-like compounds against Candida albicans orthogonally via Tor1 kinase. ACS Infect. Dis. 7(10), 2826–2835 (2021).
Medline CASGoogle Scholar
116. Vakil R, Knilans K, Andes D, Kwon GS. Combination antifungal therapy involving amphotericin B, rapamycin and 5-fluorocytosine using PEG-phospholipid micelles. Pharm. Res. 25(9), 2056–2064 (2008).
Medline CASGoogle Scholar
117. Yoshida M, Tamura K, Masaoka T, Nakajo E. A real-world prospective observational study on the efficacy and safety of liposomal amphotericin B in 426 patients with persistent neutropenia and fever. J. Infect. Chemother. 27(2), 277–283 (2021).
Medline CASGoogle Scholar
118. Zhang M, Lu J, Duan X et al. Rimonabant potentiates the antifungal activity of amphotericin B by increasing cellular oxidative stress and cell membrane permeability. FEMS Yeast Res. 21(3), foab016 (2021).
Medline CASGoogle Scholar
119. Kim JH, Chan KL, Cheng LW et al. High efficiency drug repurposing design for new antifungal agents. Methods Protoc. 2(2), 31 (2019).
Medline CASGoogle Scholar
120. Onyewu C, Blankenship JR, Del Poeta M, Heitman J. Ergosterol biosynthesis inhibitors become fungicidal when combined with calcineurin inhibitors against Candida albicans, Candida glabrata, and Candida krusei. Antimicrob. Agents Chemother. 47(3), 956–964 (2003).
Medline CASGoogle Scholar
121. Yu Q, Ravu RR, Jacob MR et al. Synthesis of natural acylphloroglucinol-based antifungal compounds against Cryptococcus species. J. Nat. Prod. 79(9), 2195–2201 (2016).
Medline CASGoogle Scholar
122. Choi JW, Lee KT, Kim S et al. Optimization and evaluation of novel antifungal agents for the treatment of fungal infection. J. Med. Chem. 64(21), 15912–15935 (2021).
Medline CASGoogle Scholar
123. Dong Y, Liu X, An Y, Liu M, Han J, Sun B. Potent arylamide derivatives as dual-target antifungal agents: design, synthesis, biological evaluation, and molecular docking studies. Bioorg. Chem. 99, 103749 (2020).
Medline CASGoogle Scholar
124. An Y, Dong Y, Liu M, Han J, Zhao L, Sun B. Novel naphthylamide derivatives as dual-target antifungal inhibitors: design, synthesis and biological evaluation. Eur. J. Med. Chem. 210, 112991 (2021).
Medline CASGoogle Scholar
125. Baugh SDP, Chaly A, Weaver DG et al. Highly potent, broadly active antifungal agents for the treatment of invasive fungal infections. Bioorg. Med. Chem. Lett. 33, 127727 (2021).
Medline CASGoogle Scholar
126. Hartmann DO, Shimizu K, Rothkegel M et al. Tailoring amphotericin B as an ionic liquid: an upfront strategy to potentiate the biological activity of antifungal drugs. RSC Adv. 11(24), 14441–14452 (2021).
Medline CASGoogle Scholar
127. Shaw KJ, Ibrahim AS. Fosmanogepix: a review of the first-in-class broad spectrum agent for the treatment of invasive fungal infections. J. Fungi (Basel) 6(4), 239 (2020).
Medline CASGoogle Scholar
128. Jacobs SE, Zagaliotis P, Walsh TJ. Novel antifungal agents in clinical trials. F1000Res 10, 507 (2021).
Medline CASGoogle Scholar
129. ClinicalTrials.gov. NCT04240886. Open-label study of APX001 for treatment of patients with invasive mold infections caused by aspergillus or rare molds (AEGIS) (2023). https://clinicaltrials.gov/ct2/show/NCT04240886 (Accessed 3 May 2023).
Google Scholar
130. ClinicalTrials.gov. NCT04148287. An open-label study of APX001 for treatment of patients with candidemia/invasive candidiasis caused by Candida auris (APEX) (2023). https://clinicaltrials.gov/ct2/show/NCT04148287 (Accessed 3 May 2023).
Google Scholar
131. Jallow S, Govender NP. Ibrexafungerp: a first-in-class oral triterpenoid glucan synthase inhibitor. J. Fungi (Basel) 7(3), 163 (2021).
Medline CASGoogle Scholar
132. Bouz G, Dolezal M. Advances in antifungal drug development: an up-to-date mini review. Pharmaceuticals (Basel) 14(12), 1312 (2021).
Medline CASGoogle Scholar
133. ClinicalTrials.gov. NCT05399641. Ibrexafungerp for the treatment of complicated vulvovaginal candidiasis (2023). https://clinicaltrials.gov/ct2/show/NCT05399641 (Accessed 3 May 2023).
Google Scholar
134. ClinicalTrials.gov. NCT05178862. A phase 3, randomized, double-blind study for patients with invasive candidiasis treated with IV echinocandin followed by either oral ibrexafungerp or oral fluconazole (MARIO) (2023). https://clinicaltrials.gov/ct2/show/NCT05178862 (Accessed 3 May 2023).
Google Scholar
135. ClinicalTrials.gov. NCT05668429. ADME study of [14∧C]-ibrexafungerp in healthy male subjects (2023). https://clinicaltrials.gov/ct2/show/NCT05668429 (Accessed 3 May 2023).
Google Scholar
136. ClinicalTrials.gov. NCT03672292. Study to evaluate the safety and efficacy of the coadministration of ibrexafungerp (SCY-078) with voriconazole in patients with invasive pulmonary aspergillosis (SCYNERGIA) (2023). https://clinicaltrials.gov/ct2/show/NCT03672292 (Accessed 3 May 2023).
Google Scholar
137. ClinicalTrials.gov. NCT03363841. Open-label study to evaluate the efficacy and safety of oral ibrexafungerp (SCY-078) in patients with candidiasis caused by Candida auris (CARES) (CARES) (2023). https://clinicaltrials.gov/ct2/show/NCT03363841 (Accessed 3 May 2023).
Google Scholar
138. ClinicalTrials.gov. NCT03059992. Study to evaluate the efficacy and safety of ibrexafungerp in patients with fungal diseases that are refractory to or intolerant of standard antifungal treatment (FURI) (2023). https://clinicaltrials.gov/ct2/show/NCT03059992 (Accessed 3 May 2023).
Google Scholar
139. Oliver JD, Sibley GEM, Beckmann N et al. F901318 represents a novel class of antifungal drug that inhibits dihydroorotate dehydrogenase. Proc. Natl Acad. Sci. USA 113(45), 12809–12814 (2016).
Medline CASGoogle Scholar
140. ClinicalTrials.gov. NCT05101187. Olorofim aspergillus infection study (OASIS) (2022). https://clinicaltrials.gov/ct2/show/NCT05101187 (Accessed 3 May 2023).
Google Scholar
141. Gow NAR, Latge JP, Munro CA. The fungal cell wall: structure, biosynthesis, and function. Microbiol. Spectr. 5(3), FUNK-0035 (2017).
Google Scholar
142. du Pre S, Beckmann N, Almeida MC et al. Effect of the novel antifungal drug F901318 (olorofim) on growth and viability of Aspergillus fumigatus. Antimicrob. Agents Chemother. 62(8), e00231-18 (2018).
MedlineGoogle Scholar
143. ClinicalTrials.gov. NCT05541107. Encochleated oral amphotericin for cryptococcal meningitis trial 3 (EnACT3) (2022). https://clinicaltrials.gov/ct2/show/NCT05541107 (Accessed 3 May 2023).
Google Scholar
144. Atukunda M KE, Rutakingirwa MK, Tugume L et al. 869. Oral encochleated amphotericin B for cryptococcal meningitis: a phase II randomized trial. Open Forum Infect. Dis. 9, ofac492.062 (2022).
Google Scholar
145. Viana R, Couceiro D, Carreiro T, Dias O, Rocha I, Teixeira MC. A genome-scale metabolic model for the human pathogen candida parapsilosis and early identification of putative novel antifungal drug targets. Genes (Basel) 13(2), 303 (2022).
Medline CASGoogle Scholar
146. Lockhart DEA, Stanley M, Raimi OG et al. Targeting a critical step in fungal hexosamine biosynthesis. J. Biol. Chem. 295(26), 8678–8691 (2020).
Medline CASGoogle Scholar
147. Demuyser L, Palmans I, Vandecruys P, Van Dijck P. Molecular elucidation of riboflavin production and regulation in Candida albicans, toward a novel antifungal drug target. mSphere 5(4), e00714-20 (2020).
MedlineGoogle Scholar
148. Shor E, Chauhan N. A case for two-component signaling systems as antifungal drug targets. PLoS Pathog. 11(2), e1004632 (2015).
Medline CASGoogle Scholar
149. Dalla Lana DF, Carvalho AR, Lopes W et al. Structure-based design of delta-lactones for new antifungal drug development: susceptibility, mechanism of action, and toxicity. Folia Microbiol. (Praha) 64(4), 509–519 (2019).
MedlineGoogle Scholar
150. Brunet K, Martellosio JP, Tewes F, Marchand S, Rammaert B. Inhaled antifungal agents for treatment and prophylaxis of bronchopulmonary invasive mold infections. Pharmaceutics 14(3), 641 (2022).
Medline CASGoogle Scholar
151. Colley T, Alanio A, Kelly SL et al. In vitro and in vivo antifungal profile of a novel and long-acting inhaled azole, PC945, on Aspergillus fumigatusinfection. Antimicrob. Agents Chemother. 61(5), e02280-16 (2017).
MedlineGoogle Scholar
152. Cass L, Murray A, Davis A et al. Safety and nonclinical and clinical pharmacokinetics of PC945, a novel inhaled triazole antifungal agent. Pharmacol. Res. Perspect. 9(1), e00690 (2021).
Medline CASGoogle Scholar
153. Murray A, Cass L, Ito K et al. PC945, a novel inhaled antifungal agent, for the treatment of respiratory fungal infections. J. Fungi (Basel) 6(4), 373 (2020).
Medline CASGoogle Scholar
154. Hashemi SM, Badali H, Faramarzi MA et al. Novel triazole alcohol antifungals derived from fluconazole: design, synthesis, and biological activity. Mol. Divers. 19(1), 15–27 (2015).
Medline CASGoogle Scholar
155. Thompson GR, Soriano A, Skoutelis A et al. Rezafungin versus caspofungin in a phase 2, randomized, double-blind study for the treatment of candidemia and invasive candidiasis: the STRIVE trial. Clin. Infect. Dis. 73(11), e3647–e3655 (2021).
Medline CASGoogle Scholar
156. Mima EG, Vergani CE, Machado AL et al. Comparison of photodynamic therapy versus conventional antifungal therapy for the treatment of denture stomatitis: a randomized clinical trial. Clin. Microbiol. Infect. 18(10), E380–388 (2012).
Medline CASGoogle Scholar
157. Minie M, Chopra G, Sethi G et al. CANDO and the infinite drug discovery frontier. Drug Discov. Today 19(9), 1353–1363 (2014).
Medline CASGoogle Scholar
158. Cong Y, Endo T. Multi-omics and artificial intelligence-guided drug repositioning: prospects, challenges, and lessons learned from COVID-19. OMICS 26(7), 361–371 (2022).
Medline CASGoogle Scholar
159. Zielinski JM, Luke JJ, Guglietta S, Krieg C. High throughput multi-omics approaches for clinical trial evaluation and drug discovery. Front. Immunol. 12, 590742 (2021). •• A discussion of the role of omics in examining cellular phnotypes, immune function and oprimization of drug development. Using single cell multiomic approaches will advance scientific understanding of immune profiles and response to therapy.
Medline CASGoogle Scholar
160. Bruch A, Kelani AA, Blango MG. RNA-based therapeutics to treat human fungal infections. Trends Microbiol. 30(5), 411–420 (2022).
Medline CASGoogle Scholar
161. Noor A PC. Amphotericin B. In: StatPearls. StatPearls Publishing, Treasure Island, FL, USA (2022). https://pubmed.ncbi.nlm.nih.gov/29493952/
Google Scholar
162. Cornely OA, Maertens J, Bresnik M et al. Liposomal amphotericin B as initial therapy for invasive mold infection: a randomized trial comparing a high-loading dose regimen with standard dosing (AmBiLoad trial). Clin. Infect. Dis. 44(10), 1289–1297 (2007).
Medline CASGoogle Scholar
163. Govindarajan A BK, Ingold CJ, Aboeed A. Fluconazole. In: StatPearls. StatPearls Publishing, Treasure Island, FL, USA (2022). https://pubmed.ncbi.nlm.nih.gov/30725843/
Google Scholar
164. Kurn H,Wadhwa R. Itraconazole. In: StatPearls. StatPearls Publishing, Treasure Island, FL, USA (2022). https://pubmed.ncbi.nlm.nih.gov/32491797/
Google Scholar
165. Peman J, Salavert M, Canton E et al. Voriconazole in the management of nosocomial invasive fungal infections. Ther. Clin. Risk Manag. 2(2), 129–158 (2006).
Medline CASGoogle Scholar
166. Greer ND. Posaconazole (Noxafil): a new triazole antifungal agent. Proc. (Bayl. Univ. Med. Cent.) 20(2), 188–196 (2007).
MedlineGoogle Scholar
167. Stone EA, Fung HB, Kirschenbaum HL. Caspofungin: an echinocandin antifungal agent. Clin. Ther. 24(3), 351–377; discussion 329 (2002).
Medline CASGoogle Scholar
168. Parish LC, Parish JL, Routh HB et al. A randomized, double-blind, vehicle-controlled efficacy and safety study of naftifine 2% cream in the treatment of tinea pedis. J. Drugs Dermatol. 10(11), 1282–1288 (2011).
Medline CASGoogle Scholar
169. Mikailov A, Cohen J, Joyce C, Mostaghimi A. Cost–effectiveness of confirmatory testing before treatment of onychomycosis. JAMA Dermatol. 152(3), 276–281 (2016).
MedlineGoogle Scholar
170. Lipner SR, Joseph WS, Vlahovic TC et al. Therapeutic recommendations for the treatment of toenail onychomycosis in the US. J. Drugs Dermatol. 20(10), 1076–1084 (2021).
MedlineGoogle Scholar

Vol. 18, No. 15

Supplemental Materials

Metrics

Downloaded 216 times

History

Received 2 December 2022

Accepted 13 June 2023

Published online 26 September 2023

Published in print October 2023

Information

Keywords

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.futuremedicine.com/doi/suppl/10.2217/fmb-2022-0269

Author contributions

All authors contributed to the manuscript writing and figures/tables preparation.

Financial & competing interest disclosure

ME Munzen, AD Goncalves Garcia and LR Martinez were supported by the National Institute of Allergy and Infectious Diseases (NIAID award no. R01AI145559) of the US NIH. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

PDF download

An update on the global treatment of invasive fungal infections

Abstract

References