Avenues for antifungal drug discovery and development: where to now?

Figures & data

Figure 1. Chemical structures of antifungal agents under clinical evaluation A) Olorofim PubChem Identifier: CID 91885568, URL: https://pubchem.ncbi.nlm.nih.gov/compound/91885568#section=2D-Structure, B) Fosmanogepix PubChem Identifier: 44123754, URL: https://pubchem.ncbi.nlm.nih.gov/compound/44123754#section=2D-Structure C) Rezafungin PubChem Identifier: 78318119, URL: https://pubchem.ncbi.nlm.nih.gov/compound/78318119#section=2D-Structure, D) Ibrexafungerp PubChem Identifier: 46871657, URL: https://pubchem.ncbi.nlm.nih.gov/compound/46871657#section=2D-Structure, E) Isavuconazonium sulfate PubChem Identifier: 72196309, URL: https://pubchem.ncbi.nlm.nih.gov/compound/72196309#section=2D-Structure.

Table 1. Representative recruiting studies.

Antifungal drug	Class	Study name	Clinical trial identifier	Study phase	Mechanism of action	Potential use
Olorofim or F901318	Orotomide	FORMULA-OLS	NCT03583164	IIb	Dihydroorotate dehydrogenase inhibition	IFIs Lomentospora prolificans Scedosporium spp. Aspergillus spp. Other Resistant Fungi
Fosmanogepix or APX001 or E1210	GPI inhibitor	AEGIS	NCT04240886	II	Gwt1 enzyme inhibition	IFIs with Candida spp Aspergillus spp. Scedosporium spp. Fusarium spp. Mucorales Cryptococcus spp. Endemic mycoses, including coccidioidomycoses
Rezafungin	Echinocandin	ReSPECT	NCT04368559	III	β 1,3 glucan synthase inhibition	Prophylaxis in HSCT and SOT Invasive infections with Candida spp. and Candida auris Aspergillus spp. Pneumocystis jirovecii
Ibrexafungerp or SCY-078	GSI	FURI, CARES, SCYNERGIA	NCT03059992, NCT03363841, NCT03672292	III, III and II	β 1,3 glucan synthase inhibition	Resistant invasive Candidiasis including Candida auris, Coccidioidomycosis Histoplasmosis Blastomycosis Resistant invasive pulmonary aspergillosis
Isavuconazole or Isavuconazonium sulfate	Triazole	Isavu-CAPA	NCT03816176, NCT04707703	II and III	14α-demethylase sterol inhibitor	Invasive aspergillosis Invasive mucormycosis Invasive candidiasis including candidemia

Invasive fungal infections (IFIs), glycosylphosphatidylinositol (GPI), GPI-anchored wall transfer protein 1 (Gwt1), hematopoietic stem cell transplant (HSCT), solid organ transplant (SOT).

Table 2. Representative antifungal agents under preclinical development.

Antifungal drug	Class	Mechanism of action	Potential use
N/A	Carboline Histone Deacetylase (HDAC) Inhibitors	Histone Deacetylase Inhibition	Combination Treatment with Fluconazole for Azole-Resistant Candidiasis [10]
Enterococcus faecalis bacteriocin, EntV	N/A	Hyphal and Biofilm Formation Inhibition	Candida albicans [13]
Haemofungin	Heme Biosynthesis Inhibitor	Ferrochelatase Inhibition	Aspergillus spp, Candida spp, Fusarium spp and Rhizopus spp [20]
Celecoxib Derivative AR-12	COX-2 inhibitor	Fungal acetyl coenzyme A (acetyl-CoA) inhibition	Combination Treatment with Fluconazole for IFIs [8]
VLL-28	Cationic Antimicrobial Peptides (CAMPs)	Cell Wall and Biofilm Targeting	Candida spp. [11]

N/A: not applicable.

Li Z, Tu J, Han G, et al. Novel Carboline Fungal Histone Deacetylase (HDAC) inhibitors for combinational treatment of azole-resistant candidiasis. J Med Chem. 2021 Jan 28; 64(2):1116–1126.

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Graham CE, Cruz MR, Garsin DA, et al. Enterococcus faecalis bacteriocin EntV inhibits hyphal morphogenesis, biofilm formation, and virulence of Candida albicans. Proc Natl Acad Sci USA. 2017 Apr 25; 114(17):4507–4512.

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Ben Yaakov D, Rivkin A, Mircus G, et al. Identification and characterization of haemofungin, a novel antifungal compound that inhibits the final step of haem biosynthesis. J Antimicrob Chemother. 2016 Apr;71(4):946–952.

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Koselny K, Green J, DiDone L, 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 Dec;60(12):7115–7127.

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Roscetto E, Contursi P, Vollaro A, et al. Antifungal and anti-biofilm activity of the first cryptic antimicrobial peptide from an archaeal protein against Candida spp. clinical isolates. Sci Rep. 2018 Dec 4; 8(1):17570.

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