Natural products have long been a rich source of antifungal agents. Recent studies have identified novel compounds, such as terpenoids and alkaloids, with potent antifungal activity (Zacchino et al., 2017; Ganeshkumar et al., 2023; Honorato et al., 2024) ( Table 1 ). A recent study demonstrated that a derivative of the natural compound nikkomycin Z exhibited strong inhibitory effects against C. auris and other resistant strains (Bentz et al., 2021). Although the inhibition of this competitive chitin synthase inhibitor (which hinders fungal cell wall synthesis) has only been tested in vitro, it offers a novel antifungal agent against Candida species (Adnan et al., 2023). Berberine is an alkaloid extracted from Berberis vulgaris that exhibits broad-spectrum antifungal activities through mechanisms such as membrane disruption, reactive oxygen species (ROS) generation, biofilm inhibition, and mitochondrial dysfunction (Li and Calderone, 2017; Ding et al., 2024). Recent studies have demonstrated the efficacy of this natural compound in targeting drug-resistant Candida species, with berberine showing significant potential in overcoming multidrug resistance in C. albicans by inhibiting the expression of the efflux pump MDR1 gene (Tong et al., 2021). Additionally, berberine displays remarkable antifungal efficacy against fluconazole-resistant C. albicans by upregulating the expression of the ATP11 gene and downregulating SOD2, which leads to increased ROS generation (Huang et al., 2022). By downregulating the expression of efflux pump genes CDR1 and MDR, as well as hypha growth-related genes, berberine significantly enhances the antifungal effects of fluconazole when used synergistically with this antifungal agent (Wu et al., 2024). Although berberine has been studied for its antifungal efficacy against various Candida species, such as C. albicans and C. glabrata, its effectiveness against C. auris has not been fully established (Xie et al., 2020; Gupta et al., 2023). This antifungal agent may hold great promise for treating multidrug-resistant strains of C. auris (Liu et al., 2020). Another significant family of natural compounds that demonstrate antifungal effects against drug-resistant strains is phenolics, which includes curcumin (found in turmeric), eugenol (derived from clove oil), and resveratrol (present in grapes) (Moghadamtousi et al., 2014; Marchese et al., 2017; Vestergaard and Ingmer, 2019). Interestingly, these three natural compounds exhibit distinct actions against fungi. Curcumin inhibits fungal biofilm formation, eugenol disrupts cell wall synthesis, and resveratrol interferes with inhibiting of yeast-hyphae morphological transition (Okamoto-Shibayama et al., 2010; Kerekes et al., 2013; Houille et al., 2014; Marchese et al., 2017; Dong et al., 2021; Lima et al., 2025). Although the antibacterial and antiviral properties of resveratrol have been established, its antifungal effects require further elucidation, as several studies have yielded conflicting results (Collado-Gonzalez et al., 2012). Furthermore, the molecular mechanisms underlying its antifungal activity remain inadequately investigated. Additionally, Jin’s laboratory identified a derivative of curcumin (Compound 4) that exhibits significant inhibition of biofilm formation and the yeast-to-hypha morphological transition. Furthermore, the synergistic combination of fluconazole and Compound 4 demonstrated over 90% anti-biofilm efficacy (32 μg/ml of Compound 4 combined with 4 μg/ml of fluconazole). Additionally, the use of these two antifungal agents inhibited nearly 90% of ATP production (Dong et al., 2021). Although this study focuses on fluconazole-resistant C. albicans, it offers a novel approach for utilizing curcumin to inhibit biofilm formation in C. auris. These findings underscore the diverse mechanisms and therapeutic potential of natural products—including terpenoids, alkaloids, phenolics, and chitin synthase inhibitors—as promising antifungal candidates against drug-resistant fungal pathogens.

Synthetic antifungal compounds, such as azoles, polyenes, and echinocandins, are widely used to combat fungal infections. However, the prolonged administration and misuse of these drugs can lead to significant drug resistance and side effects, resulting in severe consequences. Therefore, the primary objective of the next generation of antifungal drugs is to maintain the efficacy of fungal eradication while minimizing the development of resistance as much as possible ( Table 2 ). For example, the newer triazole, isavuconazole, is currently being investigated for its potential to overcome resistance mechanisms in C. auris (Nagy et al., 2021). Isavuconazole demonstrates the ability to overcome drug resistance in C. auris through mechanisms that are distinct from those of conventional azoles, such as fluconazole. Specifically, the unique molecular structure of isavuconazole contributes to its broader spectrum of binding affinity for lanosterol 14α-demethylase and enhances its stability, resulting in reduced susceptibility to mutations in the ERG11 gene and the overexpression of efflux pumps. These characteristics enable isavuconazole to effectively address both intrinsic and acquired resistance mechanisms in C. auris, positioning it as a promising alternative in cases where conventional antifungal agents exhibit diminished efficacy (Logan et al., 2022; Jangir et al., 2023). Moreover, there are several antifungal drugs are under investigation to overcome conventional drug resistance, including rezafungin, ibrexafungerp, fosmanogepix, olorofim, and opelconazole (Hoenigl et al., 2021; Espinel-Ingroff and Wiederhold, 2024). Rezafungin is classified to the member of echinocandins and under two phase III trials (ReSTORE, NCT03667690 and ReSPECT, NCT04368559). Rezafungin inhibits the activity of β-1, 3-D-glucan synthase, which disrupts the synthesis of the fungal cell wall (Garcia-Effron, 2020). In comparison to conventional echinocandins, such as caspofungin, rezafungin exhibits enhanced pharmacodynamics and pharmacokinetics, along with reduced hepatotoxicity (Ong et al., 2016). In in vitro tests, the results of the minimum inhibitory concentrations (MIC) demonstrated that rezafungin exhibited better activity against drug-resistant strains of C. auris compared to other echinocandins (Helleberg et al., 2020). Ibrexafungerp is a novel echinocandin that acts as a glucan synthase inhibitor and can be administered orally. This antifungal drug exhibits significant fungicidal activity against Candida species, including C. auris. Because the binding sites of ibrexafungerp on β-1, 3-D-glucan synthase are distinct from those of caspofungin, this antifungal agent shows great potential to circumvent cross-resistance with conventional echinocandins (Walker et al., 2011; Jimenez-Ortigosa et al., 2017). Fosmanogepix is another novel synthetic antifungal agent that is converted into the active form, manogepix, once administered to humans (Shaw and Ibrahim, 2020). This antifungal agent aims to inhibit the Gwt1 enzyme, which hinders the transport of mannoproteins to the fungal cell wall and membrane, thereby causing a loss of stability in fungal cells (Miyazaki et al., 2011). Clinically, this antifungal agent exhibits great potential for treating C. auris candidemia, and the survival rate of infected patients has significantly improved (Hoenigl et al., 2021). A multicenter, open-label, single-arm Phase 2 clinical trial was conducted in the United States in 2023. A total of 20 patients were recruited, and the survival rate reached 85% following 30 days of treatment, with no reported deaths related to fosmanogepix. Furthermore, no severe adverse effects were observed, indicating that this antifungal agent demonstrates promising safety and efficacy in the treatment of candidemia caused by the multidrug-resistant pathogen C. auris (Vazquez et al., 2023). The other two novel antifungal drugs are olorofim and opelconazole, which act as inhibitors of dihydroorotate dehydrogenase and lanosterol 14α-demethylase. These enzymes are crucial for maintaining the integrity of the fungal cell membrane; their inhibition ultimately leads to the suppression of fungal cell growth. Olorofim and opelconazole are newly developed antifungal drugs that belong to the dihydroorotate dehydrogenase enzyme inhibitor and triazole families, respectively. They have been optimized for oral and inhalation administration to treat infections caused by Aspergillus species (Kriegl et al., 2024). Additionally, several studies have demonstrated that olorofim possesses a strong ability to treat azole-resistant strains of Aspergillus fumigatus by inhibiting fungal cell growth and biofilm formation (Buil et al., 2022; Kirchhoff et al., 2022; van Rhijn et al., 2022). Thus, the research findings may provide novel strategies and perspectives for treating drug-resistant strains of C. auris. In conclusion, the development of next-generation antifungal agents, such as isavuconazole, rezafungin, and ibrexafungerp represents a critical strategy for balancing therapeutic effectiveness with the reduction of resistance development in challenging pathogens such as C. auris and A. fumigatus.

Biological antifungals, such as monoclonal antibodies (mAbs), vaccines and antifungal peptides, are emerging as novel therapeutic options ( Table 3 ). Nowadays, fungal heat shock proteins (Hsp), particularly Hsp90, are critical for the fungal stress response and survival. They are also important targets for antifungal monoclonal antibodies (mAbs).The exposed or secreted forms of Hsp90 are recognized by these mAbs, leading to the disruption of protein function, which impedes fungal growth and enhances the host immune response (Fang et al., 2025). Antifungal mAbs, such as Mycograb, are always administered alongside conventional antifungal agents like AmB. Mycograb specifically recognizes and binds to the epitope C of Hsp90 on the fungal cell wall, thereby disrupting its function, which is critical for the fungal stress response and survival, particularly under antifungal drug pressure. When used in combination with AmB, Mycograb enhances its fungicidal effects. Additionally, the presence of Mycograb supports fungal clearance by the immune system and reduces the side effects induced by AmB due to the limited drug dosage (Feng et al., 2024). The combination of Mycograb and AmB significantly decreased the mortality rate in patients with invasive candidiasis caused by Candida infections. This is evidenced by an increase in the survival rate from 48% with AmB monotherapy to 84% with combination therapy (Pachl et al., 2006). Relying on silico protein modeling and analysis, Ashraf S. Ibrahim’s research team identified a highly immunogenic and surface-exposed epitope in C. auris (hyphal-regulated protein, Hyr1p). The monoclonal antibody (mAb) was able to recognize this conserved protein across several clinical isolates of C. auris, preventing biofilm formation and enhancing opsonophagocytic killing of C. auris by macrophages. The Hyr1p-mAb significantly reduced the fungal burden and mortality rate in mice infected with lethal C. auris (Singh et al., 2023). Other identified antifungal mAbs that demonstrate significant fungal clearance in C. auris-infected mice target β-1, 2-mannotriose, hyphal wall protein 1 (Hwp1), and phosphoglycerate kinase 1 (Rosario-Colon et al., 2021, 2025). These antifungal mAbs represent a promising therapeutic option against drug-resistant strains of C. auris.

Another immunology-based therapy for the treatment of fungal infections is vaccination, which encompasses live-attenuated vaccines, pan-fungal recombinant vaccines, subunit vaccines, and conjugate vaccines (Kaur et al., 2023). The live-attenuated vaccines utilize genetically modified strains of C. albicans to elicit host immune protection. For example, PCA-2 is a C. albicans strain that exhibits resistance to caspofungin; its administration significantly increases the count of polymorphonuclear cells (PMNs) and provides protection against candidiasis in murine models. Other live-attenuated vaccine candidates include the CNC13, RML2U, and CM1613 strains of C. albicans, which have had pathogenic-related genes deleted (Kaur et al., 2023). NXT-2 serves as a representative example of a pan-fungal recombinant vaccine, which has been developed to provide significant immune protection against invasive candidiasis. The underlying principle of pan-fungal recombinant vaccines is to target common proteins found in various fungal pathogens. For instance, mannoproteins and β-glucans are essential for maintaining cell wall integrity and are present in numerous fungal species, making them attractive targets for the design of pan-fungal vaccines. The design of NXT-2 is based on the conserved amino acid sequences of the KEX1 (kexin-like protein) regions from Candida, Cryptococcus, Pneumocystis and Aspergillus (Rayens et al., 2022). In the murine model of vulvovaginal candidiasis, NXT-2 elicits localized immune responses in the vaginal mucosa that reduce the fungal burden. Furthermore, it enhances the recruitment of PMNs into the vaginal lumen (Wychrij et al., 2025). Other recombinant vaccines associated with C. albicans target two virulent proteins, Als3 and Hyr1, which are responsible for adhesion, biofilm formation, and evasion of the host immune response. The targeting of both adhesion and immune evasion through this dual-antigen fusion protein vaccine effectively prevents Candida infection and dissemination (Jia et al., 2024). The pathogenic role of Als3 has been identified in C. auris, analogous to its role in C. albicans. The N-terminus of Als3 has been developed as a vaccine (named as NDV-3A), which has demonstrated significant protective effects in immunosuppressed mice against C. auris infection (Singh et al., 2019). In 2024, Xin’s laboratory developed a vaccine against Candida by targeting the fungal cell surface proteins Fba and Met6. Short peptides derived from these two proteins were administered to a murine model using a liposomal vaccine platform known as spontaneous nanoliposome antigen particle (SNAP). The activation of SNAP was enhanced by the interaction between cobalt porphyrin phospholipid encapsulated in liposomes and three histidine residues located at the N-terminus of the synthetic short peptide immunogens. Mice immunized with SNAP-Fba+Met6 exhibited increased production of TNFα, IL-2, and IFNγ, and demonstrated a significant reduction in fungal burden in the kidneys of BALB/c mice infected with C. auris. Additionally, the SNAP vaccination provided protection to A/J mice against candidiasis challenges (Huang et al., 2024). The determination of targets, specifically fungal proteins and epitopes, for the design of vaccines is a fundamental step, as illustrated by the aforementioned examples. A research team from Germany has developed a methodology to identify novel CD4⁺ T cell epitopes with potential vaccine applications against C. auris infection. This approach utilizes the analysis of genomic databases, evolutionary information, and reverses vaccinology techniques. The team screened proteins encoded by the C. auris genome and identified several promising vaccine candidates. Furthermore, this methodology enables the exclusion of highly mutated or substituted epitopes that could compromise the efficacy of the vaccine (Gupta et al., 2022). It is essential to recognize that this approach is predominantly reliant on bioinformatics analysis; consequently, candidate vaccines must undergo evaluation through animal experimentation. Currently, vaccines specifically designed to target C. auris are less common than those developed for C. albicans. In vivo experiments and preclinical studies are still insufficient; thus, the evaluation of protective vaccines for C. auris continues to be a subject of active discussion and research.

In addition to mAbs and vaccines, small cationic peptides are also classified as biological agents that demonstrate innate antifungal activity through various mechanisms. These mechanisms include membrane disruption, inhibition of β-glucan synthase leading to cell wall disruption, induction of mitochondrial dysfunction, and the generation of reactive oxygen species. Currently, C14R, LL-37, NFAP2, and histatin-5 are well-studied antifungal peptides to against Candida infections (Fernandez de Ullivarri et al., 2020; Struyfs et al., 2021; Perez-Rodriguez et al., 2022; Velez et al., 2024). To address the challenge posed by multidrug-resistant isolates of C. auris, the research team of Firacative demonstrated that an analogue peptide of BP100, known as C14R, exhibits significant antifungal activity against 105 clinically isolated strains of C. auris that are resistant to fluconazole in Colombia. This activity is attributed to the peptide’s ability to disrupt cell membrane integrity and inhibit biofilm formation. The mean MIC values for these isolated strains were found to be 5.34 μg/ml (Velez et al., 2024). The human cathelicidin LL-37 peptide, similar to C14R, disrupts the fungal cell membrane, leading to rapid cell death and cytoplasmic leakage. Additionally, this peptide exhibits enhanced antifungal effects when used in combination with fluconazole or AmB (Rather et al., 2022). Furthermore, in contrast to the anti-Candida properties exhibited by C14R and LL-37, Dermaseptin demonstrates efficacy against four strains of C. auris by the stress and apoptosis. This peptide exhibits a strong antifungal activity with a MIC of 15.62 μg/ml (Wani et al., 2024). Neosartorya fischeri antifungal protein 2 (NFAP2) is a cysteine-rich, cationic peptide that exhibits significant anti-Candida activity. In conjunction with echinocandins, NFAP2 effectively inhibits biofilm formation in five clinical isolates of C. auris (Kovacs et al., 2021). Histatin-5, a human salivary peptide, has been identified as a potent anti-Candida auris agent. This peptide enters fungal cells through energy-dependent mechanisms, allowing it to bind to mitochondria. This interaction results in ATP leakage and the subsequent production of ROS, ultimately leading to cell death (Ganeshkumar et al., 2024). In the article published by Ruvini et al. in 2018, ten clinical isolates of C. auris were treated with histatin-5. The majority of the clinical strains, including those resistant to fluconazole, exhibited high susceptibility to histatin-5, with a killing efficiency of up to 90% at a concentration of 7.5 μM (Pathirana et al., 2018). Additionally, a study investigated the antifungal properties of human neutrophil peptide-1, human β-defensin-3, and histatin-5 against two clinical strains of C. auris. The results from FITC-Annexin V/PI staining and terminal deoxynucleotidyl transferase nick-end labeling (TUNEL) analysis indicated that human neutrophil peptide-1 and human β-defensin-3 induce both early and late apoptosis, whereas histatin-5 appears to trigger necrosis. However, it is important to note that this study was limited to only two clinical isolates and did not include in vivo experiments; thus, the full potential of these antifungal agents against C. auris may not be completely elucidated (Shaban et al., 2024). Although mAB, vaccines, and antifungal peptides have been extensively tested against various Candida species, the existing body of published studies indicates that their therapeutic efficacy against pan-resistant C. auris strains remains insufficient. Thus, further intensive in vivo and clinical studies are required to evaluate their fungicidal effects.

Nanotechnology has revolutionized the delivery of antifungal agents. The limited solubility of antifungal agents, such as fluconazole, which is only slightly soluble in water, significantly restricts their clinical applications due to their poor hydrophilic characteristics. As previously mentioned, various nanoparticles have been developed to carry or encapsulate antifungal drugs, thereby enhancing their bioavailability and antifungal efficacy. For instance, orally administered AmB nanoformulations from Martina Biopharma Inc. have undergone a Phase I clinical trial, demonstrating no severe side effects at oral doses of 200, 400, and 800 mg over a two-week period. These oral AmB nanoformulations have been evaluated for their ability to eliminate Cryptococcus from cerebrospinal fluid (CSF) in HIV patients and to treat vulvovaginal candidiasis (VVC) at dosages of 200 and 400 mg. However, the antifungal efficacy of these nanoformulations against C. auris and their final approval for clinical use may still necessitate further intensive research (Fairuz et al., 2022). Lipid-based nanoparticles, such as AmBisome^®, are extensively utilized for intravenous administration in the treatment of infections caused by Cryptococcus, Aspergillus, and Candida species. According to the recommendations from the CDC, patients should receive a dosage of 5 mg/kg intravenously once daily for the treatment of C. auris infection, particularly in cases where there is a lack of response to echinocandin therapy or in instances of persistent fungemia lasting more than five days. Additionally, recent advances include the use of lipid nanoparticles and metal-organic frameworks (MOFs) to enhance the bioavailability and efficacy of antifungal drugs were summarized in Table 4 . Targeting C. auris, nanoparticle delivery systems include lipid-based, and metal-based; both of these systems exhibited enhanced antifungal efficacy, particularly in inhibiting biofilm formation (Sutar et al., 2022; Fayed, 2024). Interestingly, one study demonstrated that silver nanoparticles exhibited fungistatic activity even without the incorporation of antifungal drugs (AlJindan and AlEraky, 2022). Moreover, zinc oxide nanoparticles serving as carriers for caspofungin demonstrated enhanced antifungal efficacy against caspofungin-resistant strains of C. auris (Fayed et al., 2021). Additionally, chitosan–PLGA (polylactide-co-glycolide) loaded with fluconazole exhibited improved drug encapsulation and prolonged release of azoles. The formulation of fluconazole loaded in chitosan-PLGA demonstrates a 64-fold increase in antifungal efficacy compared to fluconazole alone. Moreover, this fluconazole-chitosan-PLGA system showed significantly enhanced antifungal efficacy against fluconazole-resistant C. auris and C. albicans in both in vitro and in vivo models by inhibiting biofilm formation. Furthermore, the nephrotoxicity and hepatotoxicity associated with this nanoparticle-based delivery system are negligible in these nano-drug delivery systems (Kolge et al., 2023). Another critical nano-system that combats fungal infections is the lipid-based system, commonly referred to as liposomes (Marena et al., 2024). This system demonstrates significant advantages in the sustained release of drugs and enhanced bioavailability of antifungal agents. Consequently, lipid-based nano-systems have received approval from the FDA for the treatment of invasive candidiasis and aspergillosis, specifically the formulations AmBisome^®, and Abelcet^®, which contain amphotericin B (AmB) (Adedoyin et al., 2000; Stone et al., 2016; Bruggemann et al., 2022). Furthermore, the aforementioned marketed liposomal AmB formulations demonstrate properties that mitigate the nephrotoxicity associated with AmB in patients (Olson et al., 2008). Although these FDA-approved lipid-based nanosystems demonstrate significant antifungal efficacy against Candida and Aspergillus species, evidence regarding their fungicidal effects on drug-resistant strains of C. auris remains lacking.

Combination therapies utilize various FDA-approved antifungal drugs to treat fungal infections, demonstrating significant efficacy in addressing resistant fungal strains ( Table 5 ). For resistant C. auris, combination therapies have shown promise in overcoming antifungal resistance, and several clinical studies have reported positive outcomes from the combination of azoles and echinocandins (Griffith and Danziger, 2020). One study demonstrated the effectiveness of combining new drugs (diphenyl diselenide and nikkomycin Z) with currently used antifungals against C. auris. These combination therapies significantly inhibited the growth of C. auris. However, the monotherapy of these two new drugs exhibited less antifungal efficacy (Poester et al., 2022). A research team from Brown University discovered that benzodiazepines can improve the effectiveness of fluconazole and reestablish the sensitivity of azole-resistant C. albicans isolates. Notably, the exclusive application of this small molecule did not exhibit any toxic effects on fungal cells. Although this study focuses exclusively on C. albicans and does not employ animal infection models, it proposes a potential method for the synergistic use of small molecules to enhance the antifungal efficacy of traditional antifungal agents (Alabi et al., 2023). Furthermore, in addition to the combinations of two or more antifungal agents, a research team from the United States demonstrated that the synergistic use of AmB and an antiemetic drug exhibits significant anti-C. auris activities by enhancing the fungicidal activity of AmB in a very short time. They screened over 2,600 FDA-approved drugs and clinical compounds to identify rolapitant as a promoting agent that enhances antifungal effects by inducing oxidative stress, interfering with ATP production, and compromising the mitochondrial functions of C. auris (Salama et al., 2024). The same team identified that the combination of HIV protease inhibitors (lopinavir and ritonavir) with azoles (e.g., fluconazole and itraconazole) significantly reduces the burden of resistant strains of C. auris in mice (Salama et al., 2023).

Photodynamic therapy (PDT) has been widely used in cancer treatment since the 1970sand demonstrated significant efficacy in the treatment of superficial fungal infections, particularly against Candida infections. Research conducted by Hamblin et al. has focused on the application of PDT for the treatment of cutaneous infections caused by C. albicans. The study identified that the combination of methylene blue and red light (630 nm, 90 seconds per session, 4.5 J/cm²) is highly effective in reducing the fungal burden on the skin in murine models by 90%. Furthermore, this approach exhibited 100% efficacy in preventing C. albicans infections, positioning it as a rapid, non-invasive treatment strategy. Methylene blue serves as a critical photosensitizer in this synergistic approach to combat cutaneous fungal infections (Dai et al., 2011). Recently, due to the increasing prevalence of fungal infections and the rising incidence of antifungal drug-resistant cases, several research groups have sought to utilize PDT to treat C. auris infections (Bapat and Nobile, 2021). Bapat et al. investigated the antifungal effects of blue light alone, red light in conjunction with a photosensitizer, and green light combined with a photosensitizer. The results indicated that blue light alone exhibited the most significant inhibitory effect, reducing biofilm formation by 77% and disrupting mature biofilms by 57% after a 24-hour exposure, in comparison to the other two light treatments. Furthermore, the combination of blue light with photosensitizers, such as toluidine blue O, enhanced biofilm inhibition by an additional 7-22%. In the cellular and molecular level, PDT works by damaging various molecules within fungal cells through the stimulation of ROS generation. Unlike conventional antifungal agents, which target specific molecules, PDT minimizes the risk of inducing drug resistance. For instance, one study introduced the cage-modified hypocrellin as an innovative antifungal compound that demonstrates significant effectiveness against multidrug-resistant Candida species. This efficacy is underpinned by a well-defined mechanism of action, offering a promising therapeutic strategy for tackling resistant fungal infections (Liu et al., 2022). Although PDT has the potential to combat drug-resistant C. auris strains, several limitations must be acknowledged. These include the limited tissue penetration depth of activating light wavelengths, reduced efficacy against biofilm-embedded fungi due to impaired diffusion of photosensitizers, oxygen dependency in hypoxic infection sites, potential photo-toxicity to host tissues, and insufficient residual activity against fungal regrowth following treatment. These factors necessitate repeated applications, complicating clinical implementation.