Advancements and challenges in antifungal therapeutic development

Abstract

Over recent decades, the global burden of fungal disease has expanded dramatically. It is estimated that fungal disease kills approximately 1.5 million individuals annually; however, the true worldwide burden of fungal infection is thought to be higher due to existing gaps in diagnostics and clinical understanding of mycotic disease. The development of resistance to antifungals across diverse pathogenic fungal genera is an increasingly common and devastating phenomenon due to the dearth of available antifungal classes. These factors necessitate a coordinated response by researchers, clinicians, public health agencies, and the pharmaceutical industry to develop new antifungal strategies, as the burden of fungal disease continues to grow. This review provides a comprehensive overview of the new antifungal therapeutics currently in clinical trials, highlighting their spectra of activity and progress toward clinical implementation. We also profile up-and-coming intracellular proteins and pathways primed for the development of novel antifungals targeting their activity. Ultimately, we aim to emphasize the importance of increased investment into antifungal therapeutics in the current continually evolving landscape of infectious disease.

Keywords: Aspergillus; Candida; Cryptococcus; antifungal; clinical therapeutics; clinical trials; drug development; drug resistance mechanisms; fungal pathogen.

Fig 1

Antifungal susceptibility patterns of fungal pathogens highlighted on the WHO fungal priority pathogen list. Fungal pathogens are categorized by the WHO fungal priority pathogen list, ranging from critical priority to not classified. Broad susceptibility of each fungal species/genus to polyenes (POL), 5-FC, azoles (AZO), echinocandins (ECH), and ibrexafungerp (IBX) is defined as susceptible (blue), non-susceptible (gray), variably susceptible based on strain or individual drug properties (purple), or undefined (white) due to insufficient data.

Fig 2

Mechanisms of action of current clinically available antifungals. Cell membrane-targeting antifungals are depicted in (A). Polyenes act as fungicidal “sterol sponges” by forming extramembranous aggregates that extract ergosterol from lipid bilayers at the cell membrane. Amphotericin B (pictured) is an example of a polyene. Azoles exert fungistatic activity by inhibiting lanosterol 14-α-demethylase (Erg11), which blocks ergosterol biosynthesis and causes the accumulation of toxic sterol intermediates, including 14-ɑ-methyl-3,6-diol produced by Erg3. Fluconazole (pictured) is an example of an azole. Cell wall-targeting antifungals are depicted in (B). Echinocandins prevent the synthesis of (1,3)-β-D-glucan, by inhibiting the (1,3)-β-D-glucan synthase (Fks1), resulting in a loss of cell wall integrity and severe cell wall stress. Caspofungin (pictured) is an example of an echinocandin. Ibrexafungerp inhibits Fks1 by a divergent mechanism to the echinocandins. The pyrimidine analog 5-FC is depicted in (C). 5-FC is imported (green arrows) by cytosine permease where it interferes with RNA and DNA synthesis following conversion to 5-fluorouridine (5-FU) by cytosine deaminase. 5-FU is converted by uridine monophosphate (UMP) pyrophosphorylase to 5-fluorodeoxyuridine monophosphate (5-FdUMP), which inhibits thymidylate synthesis and downstream DNA biosynthesis. 5-FU is also converted by uridine UMP pyrophosphorylase to 5-FU monophosphate (5-FUMP), 5-FU diphosphate (5-FUDP), and finally 5-FU triphosphate (5-FUTP), which incorporates into RNA and interferes with translation. Adapted from reference (24).

Fig 3

Antifungal drug development timeline. Drug development can begin with a high-throughput chemical screen of a structurally-diverse chemical library (1). This is followed by the identification of the drug target through various, biochemical, genetic, and genomic approaches (2). To attain fungal selectivity, structure-guided optimization is conducted (3). Next, medicinal chemistry modifications to core scaffolds can be made to obtain optimal pharmacokinetic properties (4). Conducting mammalian models of infection (5) to evaluate the efficacy, safety, and tolerability of the drug is critical before reaching clinical trials (6). The figure was generated using BioRender.

Fig 4

Schematic of antifungal therapeutics and their mode of action. Antifungal drugs or drug classes currently approved for clinical use are in bold, while those in various stages of development are reported in plain text. Arrows with flat bases denote inhibition while brackets are used to denote proteins used in antifungal vaccinations. Generic names for fungal targets were used for consistency as not all therapies are active against one specific species. Adapted from reference (39).