Next-generation antifungal drugs: Mechanisms, efficacy, and clinical prospects

Abstract

Invasive fungal infections (IFIs) have become prominent global health threats, escalating the burden on public health systems. The increasing occurrence of invasive fungal infections is due primarily to the extensive application of chemotherapy, immunosuppressive therapies, and broad-spectrum antifungal agents. At present, therapeutic practices utilize multiple categories of antifungal agents, such as azoles, polyenes, echinocandins, and pyrimidine analogs. Nevertheless, the clinical effectiveness of these treatments is progressively weakened by the emergence of drug resistance, thereby substantially restricting their therapeutic utility. Consequently, there is an imperative need to expedite the discovery of novel antifungal agents. This review seeks to present an exhaustive synthesis of novel antifungal drugs and candidate agents that are either under current clinical investigation or anticipated to progress into clinical evaluation. These emerging compounds exhibit unique benefits concerning their modes of action, antimicrobial spectra, and pharmacokinetic characteristics, potentially leading to improved therapeutic outcomes relative to conventional antifungal regimens. It is anticipated that these novel therapeutic agents will furnish innovative treatment modalities and enhance clinical outcomes in managing invasive fungal infections.

Keywords: Antifungal compounds; Antifungal drugs; Clinical efficacy; Combination therapy strategies; Drug resistance; Immunotherapy; Invasive fungal infections; Mechanism.

Graphical abstract

Figure 1

Schematic representation of the mechanism of action of novel antifungal agents currently in clinical trials. Ibrexafungerp and rezafungin predominantly inhibit β-(1,3)-D-glucan synthase, thereby preventing glucan synthesis. Nikkomycin Z disrupts chitin biosynthesis by competitively binding to UDP-GlcNAc binding sites. Fosmanogepix exerts its activity by partially inhibiting the Gwt1 enzyme, which interferes with GPI-anchored protein biosynthesis. Opelconazole, isavuconazole, VT-1598, and oteseconazole specifically target fungal CYP51, thereby impairing ergosterol synthesis. MAT2203 and AM2-19 directly bind to ergosterol in the fungal cell membrane, leading to membrane destabilization. Olorofim primarily targets fungal dihydroorotate dehydrogenase, thus disrupting nucleic acid production and inhibiting mycelial elongation. T-2307 exerts a selective inhibitory effect on the respiratory chain complex within yeast mitochondria, resulting in a decline in mitochondrial membrane potential. (Figure created with BioRender.com).

Figure 2

The antifungal immune response is mediated through the coordinated interplay between innate and adaptive immunity. Upon fungal invasion, pattern recognition receptors (PRRs) recognize fungal cell wall components such as β-glucan, thereby initiating the phagocytic activity of effector cells, including macrophages and neutrophils, and promoting the release of pro-inflammatory cytokines, such as interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α). Subsequently, dendritic cells activate adaptive immunity by presenting fungal antigens to CD4⁺ T cells via major histocompatibility complex class II (MHC-II) molecules. This process drives the differentiation of Th1 cells, which secrete interferon-γ (IFN-γ) to enhance macrophage-mediated pathogen killing, and the activation of Th17 cells, which promote neutrophil recruitment through interleukin-17 (IL-17). B cells generate pathogen-specific antibodies, such as immunoglobulin G (IgG), facilitating opsonization and enhancing phagocytosis for effective pathogen clearance.

Figure 3

Chemical structures of novel antifungals. (A) Ibrexafungerp (C₄₄H₆₇N₅O₄·C₆H₈O₇) is a triterpenoid derivative of the natural product enfumafungin; its pharmacological efficacy is dictated by the intrinsic triterpenoid framework together with specific functional group modifications. (B) Rezafungin (C₆₅H₈₈N₈O₁₉) is developed as a derivative of Echinocandin B and features a distinct fatty acyl side chain integrated into its cyclic peptide structure. (C) Nikkomycin Z (C₂₀H₂₅N₅O₁₀) is classified as a nucleoside-peptide antibiotic that couples an uracil nucleoside with a dipeptide chain. Notably, its AHA segment bears a high degree of structural similarity to the UDP moiety of UDP-N-acetylglucosamine (UDP-GlcNAc), enabling occupancy of the chitin synthase substrate binding site, while the HPHT extension further perturbs the enzyme’s active site conformation, resulting in a dual inhibitory mechanism. (D) Fosmanogepix (C₁₈H₂₃F₂N₃O₇P₂) incorporates a bisphosphonate moiety, specifically a phosphonate oxybutoxy group, and functions as a prodrug that undergoes hydrolysis by alkaline phosphatase in vivo to yield the active compound manogepix (APX001A); this conversion releases a hydroxyl group that enhances cellular permeability. (E) Opelconazole (C₃₈H₃₇F₃N₆O₃) contains a 1H-1,2,4-triazole ring and shares the central pharmacophore with established triazole antifungals, while its long-chain hydrophobic substituent is designed to improve lipophilicity. (F) Isavuconazole (C₂₂H₁₇F₂N₅OS) features a 1H-1,2,4-triazole ring; however, the stereochemistry of its side chain (2R,3R) confers precise binding of the triazole moiety to the active site of fungal CYP51. (G) Encochleated Amphotericin B (MAT2203) (C₄₇H₇₃NO₁₇) primarily comprises amphotericin B, which is encapsulated within a nanoparticle shell formed by a phospholipid bilayer or a cholesterol complex that mimics the constituents of fungal cell membranes. (H) VT-1598 (C₃₁H₂₀F₄N₆O₂) employs a combination of a tetrazole ring and a pyridine group to achieve markedly higher affinity for fungal CYP51 relative to the corresponding human enzyme. (I) Oteseconazole (C₂₃H₁₆F₇N₅O₂) is structurally optimized with a tetrazole moiety, multiple fluorine substituents, and a refined stereochemical configuration, thereby enhancing its selectivity toward fungal CYP51. (J) Olorofim (C₂₈H₂₇FN₆O₂) incorporates essential structural features, including interconnected polycyclic elements and a moiety that selectively binds to the CBD region of dihydroorotate dehydrogenase (DHODH), resulting in potent and selective inhibition of the fungal enzyme. (K)VL-2397 (C₄₀H₅₉AlN₁₀O₁₃) is characterized by a cyclic hexapeptide backbone, an aluminum-chelating center, and siderophore-mimetic attributes, which collectively underlie its pharmacological activity.

Figure 4

Development of novel antifungals. The development process of new antifungal drugs currently in clinical trials, including basic research stage, animal experiment stage, clinical trial stage and official marketing stage.