The evolution of antifungal therapy: Traditional agents, current challenges and future perspectives

Abstract

Fungal infections kill more than 3 million people every year. This high number reflects the significant challenges that treating these diseases worldwide presents. The current arsenal of antifungal drugs is limited and often accompanied by high toxicity to patients, elevated treatment costs, increased frequency of resistance rates, and the emergence of naturally resistant species. These treatment challenges highlight the urgency of developing new antifungal therapies, which could positively impact millions of lives each year globally. Our review offers an overview of the antifungal drugs currently available for treatment, presents the status of new antifungal drugs under clinical study, and explores ahead to future candidates that aim to help address this important global health issue.

Keywords: Antifungal drug development; Antifungal drugs; Antifungal therapy.

Graphical abstract

Fig. 1

Representation of classical antifungal drugs, their mechanisms of action and respective dates of discovery. Polyenes (1949): bind to ergosterol in the fungal cell membrane, forming pores that compromise cell integrity. Flucytosine (1957): once metabolized into 5-fluorouridine triphosphate, incorporates into fungal RNA, replacing uridylic acid and inhibiting RNA/DNA synthesis. Azoles (1969): inhibit the activity of the enzyme lanosterol 14-α-demethylase, disrupting ergosterol synthesis and compromising membrane integrity. Echinocandins (1987): bind to the β-(1,3)-d-glucan synthase subunit Fks1p, blocking its activity and inhibiting the synthesis of β-(1,3)-d-glucan, a critical structural component of the fungal cell wall. The cellular targets of each class are highlighted in a schematic representation of the fungal cell.

Fig. 2

Representation of the main antifungal resistance mechanisms. Each pathway highlights specific genetic mutations and cellular processes that contribute to resistance. Azole resistance occurs when Erg11 is overexpressed counteracting the effect of the azole and permitting ergosterol synthesis, additionally Erg11 mutations impede the binding of the azole; mutations in Erg3 prevent the accumulation of other toxic sterols; aneuploidies in chromosome 5, forming an isochromosome i5(L) lead to an increased number of copies of Erg11; the increased presence of ABC and MSF transporters reduces the intracellular drug concentration. Echinocandins resistance arises when Fks is mutated blocking the echinocandin binding and chitin synthesis upregulation, which helps to maintain the cell wall structure. Polyenes resistance emerges when different ERG genes are mutated, allowing the synthesis of alternative sterols shifting the cell membrane composition. RNA/DNA synthesis inhibitor resistance originates when transport and metabolism genes are mutated, impeding the importation of the drug to the nucleus; the increased pyrimidine production, diminishes the effect of the drug.

Fig. 3

Representation of recently developed antifungal drugs and their mechanisms of action. Fosmanogepix (2016): inhibits the enzyme Gwt1, which is involved in the trafficking and anchoring of mannoproteins, essential components of the fungal cell wall. Encochleated AmB (2019): shares the mechanism of action of classic AmB (ergosterol binding and pore formation), but the drug molecules are encapsulated with calcium ions within a lipid bilayer sheet, rolled into a spiral structure. Ibrexafungerp (2021): inhibits β-(1,3)-d-glucan synthase, disrupting the synthesis of β-(1,3)-d-glucan, a vital structural component of the fungal cell wall. Olorofim (2021): inhibits dihydroorotate dehydrogenase (DHODH), a critical enzyme for pyrimidine biosynthesis. Oteseconazole (2022), VT-1598 (2022), and Opelconazole (2021): inhibit lanosterol 14-α-demethylase, impairing ergosterol synthesis and compromising membrane integrity. These drugs have a mechanism of action similar to azoles but with structural and functional improvements. Rezafungin (2023): a novel echinocandin, also inhibits β-(1,3)-d-glucan synthase, targeting fungal cell wall synthesis. The figure includes a timeline highlighting the drugs’ latest FDA status, either as orphan or approved drugs, alongside a schematic representation of their specific cellular targets in the fungal cell.