Multidrug Resistance and Host Adaptation in Candida Auris: From Molecular Mechanisms to Emerging Therapeutic Frontiers

Abstract

C. auris is an emerging multidrug-resistant (MDR) fungal pathogen that poses an urgent threat to global public health. It is characterized by rapid nosocomial transmission, persistent environmental survival, and extensive cross-resistance to conventional antifungal therapies. This comprehensive narrative review bridges the fundamental molecular mechanisms of intrinsic and acquired antifungal resistance with host adaptation strategies and emerging clinical interventions. C. auris resistance is driven by a highly sophisticated network of genetic mutations and metabolic reprogramming distributed across six geographically distinct clades (I–VI), including the newly identified Clade VI from the Indomalayan zone. Azole resistance primarily relies on clade-specific point mutations in the target gene ERG11, synergistically amplified by TAC1b-driven transcriptional upregulation of the CDR1 efflux pump. Echinocandin resistance is predominantly mediated by conformational reshaping across three distinct hotspot regions of the FKS1 gene, bolstered by Hsp90-mediated stress compensatory networks. For polyenes, while clinical resistance is frequently overestimated by commercial assays, true tolerance mechanisms involved the depletion of target ergosterol and profound non-sterol-dependent sphingolipid remodeling. Beyond genomic modifications, C. auris exhibits significant phenotypic plasticity, forming robust, polysaccharide-rich biofilms on indwelling medical devices that confer profound physical drug tolerance. Clinically, the fungus demonstrates a strong cutaneous tropism-predominantly colonizing the axilla and groin-which acts as the primary reservoir for hospital outbreaks. Furthermore, experimental models reveal that C. auris actively exploits host immune deficiencies, specifically subverting the IL-17A/neutrophil/S100A8 axis, to evade immune clearance and establish persistent colonization. To overcome these formidable MDR bottlenecks, therapeutic paradigms are rapidly evolving. The integration of next-generation antifungals such as the long-acting echinocandin rezafungin, fosmanogepix, and ibrexafungerp, synergistic combination therapies, quorum-sensing inhibitors such as farnesol, and experimental nanocarrier delivery systems could represent promising frontiers to effectively dismantle the complex defense networks of C. auris.

Introduction

Over the past decade, C. auris (Candidozyma auris) has emerged as a formidable hospital-associated fungal pathogen, triggering widespread nosocomial outbreaks globally at an unprecedented pace. Characterized by its adaptability to clinical environmental surfaces, high mortality rates among vulnerable populations, and extensive cross-resistance to conventional antifungal agents, C. auris poses a severe challenge to modern healthcare systems [1–3], which has been acknowledged as an urgent threat by the Centers for Disease Control and Prevention [4]. The recently published 2025 global guidelines by the European Confederation of Medical Mycology (ECMM), in cooperation with ISHAM and ASM, and consensus report developed by a collaboration between several Turkish medical societies, both further emphasize the need for updated, comprehensive management strategies to combat the rapid emergence of this difficult-to-treat pathogen [5, 6].

From an epidemiological and phylogenetic perspective, C. auris does not represent a single global clone but rather exhibits geographic evolutionary diversity spanning all six continents. Currently, the global population is categorized into six distinct evolutionary clades: Clade I (South Asia), Clade II (East Asia), Clade III (Africa), Clade IV (South America), Clade V (Iran) [7], and the recently characterized Clade VI, which is identified in Singapore and Bangladesh within the Indomalayan zone [8]. Understanding the genomic variations across these clades was crucial, as they exhibit different mutational fingerprints and resistance trajectories. For instance, while earlier reports suggested high genetic uniformity in Clade I, comprehensive genomic investigations reveal significant genetic variability. Some Clade I isolates are fully wild-type, whereas others harbor specific acquired mutations in resistance-associated genes such as ERG11 and the transcription factor TAC1b.

To comprehend the antifungal resistance landscape of C. auris, it is vital to delineate intrinsic resistance from acquired resistance. Intrinsic resistance refers to the inherently high minimum inhibitory concentrations observed naturally in certain lineages, such as the notably high baseline fluconazole resistance characteristic of Clades I, III, and IV [9]. In contrast, acquired resistance could develop under selective therapeutic pressure, driven by genetic mutations and metabolic reprogramming. Furthermore, fluconazole resistance for clade I and III is always high, amphotericin B resistance overall seems not to increase, and global surveillance indicated that echinocandin resistance was not yet widespread, typically ranging between 0 and 8% [10]. Similarly, while amphotericin B resistance is frequently reported, these rates are often overestimated by commercial susceptibility assays due to MIC values hovering near cutoff points, necessitating careful interpretation based on updated tentative breakpoints.

Beyond genomic resistance, the fundamental drivers of the persistent hospital-acquired infections caused by C. auris lies in its phenotypic plasticity, environmental resilience, and tissue tropism. Clinically, C. auris predominantly colonized the skin, particularly the axilla and groin, making rigorous admission screening of these sites a cornerstone of current infection control guidelines [5]. In such niches, C. auris could exhibit sophisticated immune evasion strategies, including the circumvention of neutrophil chemotaxis and antimicrobial defense mechanisms, thereby facilitating long-term host colonization.

Faced with the multifaceted challenges posed by this superbug, an in-depth analysis of its molecular evolution, collective tolerance, and host–pathogen interactions is of importance. Therefore, this comprehensive narrative review aims to systematically elucidate the multidimensional mechanisms of C. auris resistance. By bridging the fundamental molecular mechanisms of antifungal resistance with biofilm-mediated phenotypic tolerance and host immune evasion, this review underscores their direct implications for clinical resistance and therapeutic management. Ultimately, we would explore emerging, innovative therapeutic ways-ranging from novel mechanism-of-action drugs to nanotechnology-aimed at dismantling the defense systems of C. auris and providing key theoretical foundations for future clinical interventions.

Molecular Diagnostics and Direct Detection

Recently, molecular diagnostics enabled rapid, direct Candida auris detection. Real-time quantitative PCR (qPCR) targeting the ITS2 region achieves results from primary specimens within four hours, demonstrating 89% sensitivity, 100% specificity, and a 1-CFU/reaction limit of detection (LOD) [11]. Concurrently, multiplex PCR could reliably differentiate C. auris from phylogenetically related species, while portable loop-mediated isothermal amplification (LAMP) facilitated accessible, thermocycler-free screening [12, 13]. Automated microfluidic platforms further streamline point-of-care testing, delivering results in 3–4 h for critical care triage, pending future cost optimizations [14]. Additionally, MALDI-TOF MS significantly accelerate culture-dependent workflows. Utilizing formic acid extraction, it identifies isolates and geographic clades with 98.9% accuracy within three hours [15]. Furthermore, AI-driven spectral analysis elevates this accuracy to 99.4%–100% for high-throughput epidemiological surveillance. However, MALDI-TOF MS remained fundamentally constrained by its reliance on isolated colonies, precluding its utility for low-titer direct primary sample analysis [16].

Molecular Mechanisms of Antifungal Resistance

The evolutionary success of C. auris is largely driven by its highly plastic and multifaceted resistance repertoire. The mechanisms underpinning its resistance to the three major antifungal classes-azoles, echinocandins, and polyenes-extend far beyond simple drug-target interactions, encompassing complex transcriptional regulatory networks, global metabolic reprogramming, and systemic stress compensatory responses (Fig. 1) (Table 1).

Fig. 1.

Cellular and molecular mechanisms of multidrug resistance in Candida auris. (A) Azole Resistance: Fluconazole efficacy is abrogated via target site alterations and enhanced cellular efflux. Point mutations in the ERG11 gene (e.g., Y132F, K143R) alter the binding affinity of lanosterol 14α-demethylase, preventing azole interaction while preserving ergosterol biosynthesis. Concurrently, upregulated ATP-dependent Cdr1 ABC transporters actively expel the drug, drastically reducing intracellular concentrations. (B) Echinocandin Resistance: Resistance to echinocandins (e.g., caspofungin, micafungin) is primarily mediated by specific mutations (e.g., S639F) in the FKS1 subunit of the 1, 3-β-D-glucan synthase complex. This desensitizes the enzyme, preventing drug-induced glucan inhibition and cell wall lysis, supported by a compensatory thickening of the cell wall chitin layer. (C) Polyene Resistance: Amphotericin B resistance is characterized by membrane lipid remodeling. A severe depletion of the target ergosterol, coupled with compensatory increases in sphingolipids, prevents effective drug binding, subsequent pore formation, and lethal intracellular ion (K⁺, Na⁺) leakage. (D) Central to the multidrug-resistant phenotype are transcriptional regulators. Gain-of-function mutations in the TAC1b transcription factor (e.g., A640V) drive the significant upregulation of CDR1 transcription. This regulatory cascade directly increases Cdr1 efflux pump abundance

Table 1.

Summary of major antifungal classes and potential molecular mechanisms of resistance in C. auris

Antifungal class (Representative agents)	Potential mechanism of action	Primary resistance mechanism	Key genes & specific alterations	Clade specificity & systemic factors
Azoles (Fluconazole)	It could inhibit lanosterol 14α-demethylase, a critical enzyme in the ergosterol biosynthesis pathway	Target site modification (diminished binding affinity) and dynamic intracellular drug efflux (efflux pump upregulation)	Target mutation: ERG11: Y132F, K143R, F126L Efflux/Regulation: CDR1: Overexpression TAC1b: A640V (gain-of- function)	Y132F: Clades I (South Asia) & IV (South America) F126L: Clade III (Africa) K143R: Clades I & IV Note: TAC1b mutations frequently co-occur with ERG11 mutations in Clade I isolates, causing synergistic resistance
Echinocandins (Caspofungin, Micafungin, Rezafungin)	They may non-competitively inhibit the catalytic subunit of the 1,3-β-D-glucan synthase complex, disrupting cell wall integrity	Adaptive reshaping of the target enzyme (spatial conformational changes) and robust stress compensatory networks	Target mutation: FKS1: Mutations across HS1, HS2, HS3 hotspots (e.g., S639F, S639P) Stress compensation: Hsp90 (salvage pathway stabilization)	S639F/S639P could be the prevalent markers of high- level resistance, especially in Clade I Systemic: Hsp90 stabilizes calcineurin signaling, driving compensatory upregulation of alternative cell wall components (e.g., chitin)
Polyenes (Amphotericin B)	It may extract ergosterol from the fungal cell membrane to form extra-membranous "sponges", inducing lethal ion leakage and oxidative stress	Sterol-dependent mechanisms, global lipid/sphingolipid metabolic reprogramming (membrane rigidification), and oxidative stress mitigation	Sterol/Lipid pathway: ERG6: YY98V UPC2: S332R HSX11: Downregulation ROS mitigation: AOX2: Upregulation (driven by RTG3/UPC2)	Shifts membrane profile toward cholesta-type sterols lacking AMB binding prerequisites Reduces glucosylceramides while accumulating α- hydroxyceramides Systemic: Neutralizes reactive oxygen species (ROS) while maintaining mitochondrial respiration

AMB, Amphotericin B; ROS, Reactive Oxygen Species; HS, Hotspot

Azole Resistance: Clade-Specific Target Mutations, Efflux Pump Upregulation, and Transcriptional Regulatory Networks

Azole antifungals, predominantly fluconazole, exert their fungistatic effects by inhibiting lanosterol 14α-demethylase (encoded by the ERG11 gene), a critical enzyme in the ergosterol biosynthesis pathway. In C. auris, acquired azole resistance is prevalent and governed by a sophisticated interplay between target site modification and dynamic intracellular drug efflux.

Primarily, solitary mutations in a single gene, such as Y132F or K143R, are capable of conferring azole resistance independently. These missense mutations induced critical conformational changes in lanosterol 14α-demethylase, diminishing the binding affinity of azoles to the target enzyme. Notably, distinct ERG11 mutations may map to specific geographic clades, highlighting the divergent evolutionary trajectories of C. auris globally. For instance, the Y132F substitution may be associated with Clade I (South Asia) and Clade IV (South America) [17, 18], whereas the F126L mutation was characteristic of Clade III (Africa) [19], and the K143R variant is frequently identified in both Clade I and Clade IV [20, 21]. The recently characterized Clade VI (Indomalayan zone) further underscores the geographic variability of these resistance markers, necessitating clade-specific genomic surveillance.

Beyond target modification, the pronounced upregulation of multidrug efflux pumps constituted a formidable barrier to azole efficacy. Genomic and transcriptomic analyses indicated that ATP-binding cassette (ABC) transporters, most notably the pump encoded by CDR1, were significantly overexpressed in resistant isolates, actively extruding azoles and preventing them from reaching inhibitory intracellular concentrations. Crucially, this efflux surge could be not an isolated event but is orchestrally driven by mutations in transcription factors. Gain-of-function mutations in the zinc-cluster transcription factor TAC1b (e.g., A640V), which frequently co-occur with ERG11 mutations in Clade I isolates, lead to the constitutive hyperactivation of downstream target genes, including CDR1 [22, 23]. This synergistic dual-mechanism-target modification combined with transcription-driven efflux hyperactivation-provides a comprehensive explanation for the profound clinical fluconazole resistance observed in C. auris.

Echinocandin Resistance: Conformational Remodeling Across FKS1 Hotspots and Stress Compensatory Networks

Echinocandins (e.g., caspofungin, micafungin, rezafungin) are the recommended first-line therapeutics for invasive candidiasis. They act by non-competitively inhibiting the catalytic subunit of the 1,3-β-D-glucan synthase complex, thereby disrupting cell wall integrity. Although global echinocandin resistance in C. auris remains relatively low (typically under 8%) [10], its emergence is a critical clinical concern.

The most direct molecular driver of echinocandin resistance is the adaptive reshaping of the target enzyme, encoded by the FKS1 gene. While initial reports primarily focused on a single region, it is now established that resistance-conferring non-synonymous mutations occur across three distinct, highly conserved hotspot regions, encompassing residues 639–647 in HS1, 1354–1357 in HS2 and 690–700 in HS3 of the FKS1 gene [24, 25]. Among these, modifications within HS1-particularly the S639F and S639P substitutions-are the prevalent markers of high-level echinocandin resistance, especially within Clade I [24, 26, 27]. Missense mutations within the HS1 hotspot region, such as R1354H [28], G7S, P11H [29], could be correlated with elevated MICs and in vivo therapeutic failure. These specific amino acid replacements induce significant spatial conformational changes in the glucan synthase complex, which may impaire the binding affinity of echinocandins, including the newer extended-half-life agent rezafungin.

Furthermore, C. auris bolsters its survival against echinocandin-induced cell wall damage through robust stress compensatory networks. Upon pharmacological disruption of glucan synthesis, the fungal cell rapidly activates salvage pathways mediated by heat shock proteins, prominently Hsp90 [30]. Acting as a biological capacitor, Hsp90 stabilizes downstream signaling cascades, including the calcineurin pathway, which subsequently drives a compensatory upregulation of alternative cell wall components, such as chitin [31]. This dynamic interplay between FKS1 target reshaping and Hsp90-mediated cell wall fortification highlights the potential of developing Hsp90 or calcineurin inhibitors as synergistic adjunctive therapies.

Polyene Resistance: Ergosterol Sequestration, Sphingolipid Reprogramming, and Oxidative Stress Mitigation

The specific molecular drivers of Amphotericin B (AMB) resistance in C. auris were not yet fully elucidated, which may operate by extracting ergosterol from the fungal cell membrane to form extra-membranous "sponges," thereby compromising membrane integrity and inducing lethal ion leakage and oxidative stress. Historically, high rates of AMB resistance were reported. However, it is imperative to note that commercial susceptibility assays often overestimate AMB resistance due to MIC values hovering near cutoff points. Evaluated against the tentative epidemiological cutoff values (ECV of 2 mg/L) defined by the CDC and European Committee on Antimicrobial Susceptibility Testing (EUCAST) [32], true AMB resistance was less ubiquitous but remains a formidable clinical challenge.

While our current understanding of the precise molecular drivers of AMB resistance in C. auris is still incomplete, recent multi-omics studies have illuminated a highly complex, multigenic landscape. Traditional sterol-dependent resistance mechanisms involve mutations in ERG6 (e.g., the YY98V substitution) [33] or the UPC2 transcription factor (e.g., S332R) [34]. These mutations alter the ergosterol biosynthetic output, shifting the membrane sterol profile toward cholesta-type sterols, which lack the structural prerequisites for effective AMB binding and extraction.

Moreover, recent evidence indicated the critical role of sterol-independent mechanisms, particularly global lipid metabolic reprogramming. Drug-resistant C. auris isolates frequently showed significant alterations in membrane sphingolipid (SL) composition. For instance, the downregulation of HSX11-a gene involved in SL biosynthesis-leads to a drastic reduction in glucosylceramides and an accumulation of α-hydroxyceramides. This deep structural remodeling of the lipid membrane biophysically altered the accessibility and binding affinity of AMB to its membrane targets [34].

Additionally, AMB resistance is heavily reinforced by oxidative stress mitigation pathways. AMB exposure typically triggers the accumulation of lethal reactive oxygen species (ROS). In resistant C. auris, the compensatory upregulation of alternative oxidase 2 (AOX2), driven by retro-grade signaling regulators like RTG3 and UPC2, effectively neutralizes AMB-induced oxidative damage while maintaining mitochondrial respiration [35]. The convergence of targeted sterol depletion, sphingolipid-mediated membrane rigidification, and AOX2-driven ROS mitigation exemplifies the highly sophisticated, systems-level defense mechanisms employed by C. auris against polyene antifungals [34].

Phenotypic Plasticity and Biofilm-Mediated Tolerance

While genomic mutations constituted the primary drivers of intrinsic and acquired antifungal resistance, the clinical intractability of C. auris was heavily compounded by its phenotypic plasticity and capacity for biofilm formation. It was crucial to distinguish between these two phenomena. Unlike genetic resistance, which was governed by inheritable DNA sequence variations (e.g., ERG11 or FKS1 mutations), biofilm-associated tolerance was a transient, population-level phenotypic state characterized by profound metabolic shifts and the construction of formidable physical barriers.

Clinically, the propensity of C. auris to form robust biofilms on host mucosal tissues, skin, and abiotic surfaces-most notably indwelling medical devices such as central venous catheters (CVCs) and urinary catheters-is a primary catalyst for refractory nosocomial outbreaks and treatment failures. Biofilms significantly elevate the survival threshold of the fungal population, rendering them highly recalcitrant to standard antifungal regimens and external stressors, including photodynamic therapy [36, 37]. Recognizing the profound clinical impact of device-associated biofilms, the 2025 ECMM/ISHAM/ASM global guidelines strongly emphasize rapid source control, strictly recommending the prompt removal of central venous and urinary catheters in candidemia patients whenever safely feasible.

At the biochemical level, the extracellular matrix (ECM) serves as the core physical barrier underpinning biofilm tolerance. Recent ultrastructural analyses indicate that the C. auris biofilm matrix is heavily enriched with complex mannan-glucan polysaccharides. This dense, highly viscous network acts as a molecular sieve, effectively sequestering up to 70% of azole antifungals within its outer layers and preventing lethal drug concentrations from reaching the metabolically dormant persister cells residing deep within the biofilm core [38]. Furthermore, extracellular vesicles (EVs) actively secreted by the embedded fungal cells play an indispensable role in biofilm biogenesis and maintenance. These EVs continuously traffic essential matrix proteins, lipid components, and polysaccharides into the extracellular space, dynamically fortifying the structural integrity of the biofilm against pharmacological and environmental attacks.

Phenotypic plasticity, specifically the pathogen’s ability to transition between "aggregative" and "non-aggregative" states, further exacerbates this population-level tolerance. C. auris clinical isolates frequently exhibit an aggregative phenotype that grants exceptional adaptability to hostile microenvironments. Integrated transcriptomic and functional studies reveal that aggregative strains constitutively upregulate specific cell surface adhesins, such as Als4 and Scf1 [39]. These adhesins mediate intense cell-to-cell adhesion and coaggregation, stabilizing the intricate three-dimensional architecture of the biofilm. This tight intercellular aggregation not only severely restricts the physical penetration of antifungal agents but also provides a robust natural shield, allowing the fungal clusters to effectively evade recognition and phagocytosis by host immune cells.

Finally, the unique microenvironment within the biofilm triggers profound transcriptional reprogramming that amplifies the overarching resistance phenotype. During biofilm maturation, genes encoding major facilitator superfamily (MFS) and ATP-binding cassette (ABC) transporter proteins-key efflux pumps such as CDR1-are heavily upregulated, acting synergistically with the ECM barrier to expel any internalized drugs. Despite this daunting defense network, recent therapeutic explorations into quorum-sensing (QS) modulation offer a promising strategy to reverse biofilm tolerance. Endogenous QS molecules, such as farnesol, have been shown to significantly impair surface adhesion and halt early biofilm formation in vitro. Crucially, farnesol effectively downregulates the expression of both pathogenic adhesins and efflux pumps within the biofilm architecture. Utilizing such natural adjuvants or QS inhibitors to dismantle the phenotypic defenses of C. auris could be rescuing the efficacy of existing antifungals against multidrug-resistant (MDR) biofilms.

Host Immune Defense and Microenvironment-Driven Colonization

The fundamental driver of the relentless nosocomial transmission and widespread dissemination of C. auris extends beyond its multidrug resistance profile, lying predominantly in its extraordinary capacity for persistent host colonization and environmental survival.

Clinically, C. auris exhibits a profound tropism for the skin, distinguishing it from other Candida species that primarily target the gastrointestinal or genitourinary tracts. In actual patient populations, the axilla and groin serve as the predominant and most clinically relevant anatomical reservoirs for prolonged colonization. This robust cutaneous colonization leads to continuous fungal shedding, heavily contaminating healthcare environments, shared medical equipment, and indwelling devices. Recognizing the critical epidemiological significance of these specific colonization niches, the newly established 2025 ECMM/ISHAM/ASM global guidelines showed active surveillance utilizing composite screening swabs from the axilla and groin upon patient admission [5]. Identifying such localized colonization is now considered the cornerstone of infection prevention, enabling the rapid implementation of isolation protocols to thwart hospital-wide outbreaks.

Beyond cutaneous niches, in vivo experimental models have yielded vital mechanistic insights into how C. auris adapts to and subverts host immune defenses within deeper mucosal microenvironments. Although clinically symptomatic vaginal candidiasis caused by C. auris is rarely reported in human patients, murine models simulating microaerophilic mucosal conditions (such as vulvovaginal candidiasis, VVC) have demonstrated that multiple major circulating lineages (particularly Clades I, III, and IV) possess an inherent, highly adapted capacity to establish persistent mucosal colonization [40]. In these host–pathogen interactions, the interleukin-17A (IL-17A) signaling pathway acts as a crucial protective immunological barrier.

Experimental evidence indicates that in IL-17A-deficient host microenvironments, the local fungal burden is significantly exacerbated, accompanied by a profound impairment in neutrophil chemotaxis and tissue infiltration. Crucially, this localized immune defect leads to a precipitous decline in the secretion of S100A8, a key host defense calprotectin endowed with potent chemotactic and direct antimicrobial activities [40]. Under immunocompetent conditions, local S100A8 concentrations positively correlate with the recruitment of inflammatory cells and inversely correlate with the fungal burden. The attenuation of this response in compromised hosts illuminates a highly sophisticated evasion strategy: C. auris exploits host immune deficiencies-particularly functional defects within the IL-17A/neutrophil/S100A8 axis-to circumvent immune recognition, evade neutrophil-mediated phagocytosis, and bypass S100A8-mediated killing [40]. Consequently, this immune subversion enables the pathogen to secure long-term, persistent colonization in highly vulnerable, immunocompromised hosts.

Frontier Interventions to Overcome Resistance Bottlenecks of C. Auris

The relentless emergence of multidrug-resistant and pandrug-resistant C. auris isolates has rendered conventional antifungal therapies increasingly ineffective, driving an urgent global search for innovative therapeutic strategies. As a critical-priority pathogen on the WHO Fungal Priority Pathogens List, C. auris exhibits resistance rates approaching 90% for azoles, 30–50% for amphotericin B, and emerging resistance to echinocandines. This resistance crisis has catalyzed the development of frontier interventions spanning novel chemical entities, biological therapeutics, nanotechnological delivery systems, and immunoprophylactic strategies. Here, we synthesize the most promising approaches that collectively address the resistance bottlenecks of this formidable pathogen (Table 2).

Table 2.

Potential frontier therapeutic interventions against multidrug-resistant C. auris

Intervention class	Agent/strategy	Potential mechanism of action	Key characteristics & efficacy against C. auris	Development stage
Clinical-stage antifungals	Rezafungin	Echinocandin. It may inhibit 1,3-β-D-glucan synthase (same binding site as conventional echinocandins)	Long-acting (t1/2 133 h) allowing once-weekly IV dosing. Good in vitro activity, though FKS-mutant resistance occurs	Phase III (ReSTORE)
	Ibrexafungerp	Triterpenoid. It could inhibit 1,3-β-D-glucan synthase at a distinct binding site	Retains activity against FKS-mutant strains resistant to traditional echinocandins	Phase III (CARES)
	Fosmanogepix (FMGX)	Gwt-1 inhibitor. It may disrupt GPI-anchored wall transfer protein-1	Potent against MDR/pandrug-resistant isolates (MIC50/90: 0.004–0.008 μg/mL). Dual IV/oral formulations	Phase II
	Olorofim	Orotomide. It might inhibit fungal dihydroorotate dehydrogenase	Activity extends to C. auris. Evaluated primarily for invasive mold diseases	Phase III (OASIS)
Novel compounds & natural products	Coniotins (A-D)	Lipopetaibiotics (from Coniochaeta hoffmannii)	Ultra-strong synergy with caspofungin (reduces MIC to breakpoint). It extended lifespan in C. elegans models	Preclinical
	Gua-SMACS-16	Cationic supramolecule. It may disrupt cytoplasmic membrane (β-glucan dependent)	Ultra-strong synergy with caspofungin against C. auris (FICI < 0.034)	Preclinical
Anti-virulence peptides	EntV-derived peptides	It may inhibit hyphal morphogenesis and biofilm formation without exerting selective pressure	Stapled variants display high serum stability (t1/2 33 h). It could reduce fungal burden in murine candidiasis models	Preclinical (In vivo)
Nanoparticle systems (Anti-Biofilm)	Amphotericin B nanoemulsions (NEA)	It may enhance biofilm penetration via approximately 40 nm droplet size	Superior antibiofilm activity compared to free AMB (reduces viability to 17% at0.19 μg/mL)	Preclinical
	Silver Nanoparticles (AgNPs)	They may release Ag+ ions and generates ROS; disrupts biofilm integrity	Eradicates preformed biofilms (IC50 0.48 ppm) and inhibits initial adhesion	Preclinical
	Zinc Oxide (ZnO) NPs	It could downregulate adhesion gene ALS5	Interferes with cell adhesion and subsequent biofilm development	Preclinical
	Bismuth NPs	It might disrupt cell morphology and biofilm architecture	Relatively low toxicity; broad activity across clades (IC50 5.1–113.1 μg/mL)	Preclinical
Vaccines (Immunoprophylaxis)	β-Glucan chitosan particle (GCP)	It may induce anti-GCP antibodies targeting cell wall N/O-linked glycans	Elicits protective Th2/Th17-polarized response. Significantly reduces fungal burden and tissue lesions in mice	Preclinical (In vivo)

AMB, Amphotericin B; FICI, Fractional Inhibitory Concentration Index; GPI, Glycosylphosphatidylinositol; MDR, Multidrug-resistant; MIC, Minimum Inhibitory Concentration; NP, Nanoparticle; ROS, Reactive Oxygen Species

Clinical-Stage Antifungals

Recent regulatory approvals and late-stage clinical trials have introduced several agents with potent activity against C. auris, could offer alternatives to first-line echinocandins. Rezafungin, a novel long-acting echinocandin with a half-life of approximately 133 h enabling once-weekly intravenous administration, has the binding sites are the same as other echinocandins. It showed non-inferiority to caspofungin in the Phase III ReSTORE trial for candidemia and invasive candidiasis, with faster fungemia clearance observed in the rezafungin arm [41, 42]. Although rezafungin shows good in vitro activity against C. auris isolates, a small percentage (6.6%, 8/121) of isolates exhibited resistance with FKS target gene mutations [43]. Ibrexafungerp represents the new antifungal class in over two decades-a triterpenoid glucan synthase inhibitor that binds at a distinct site from echinocandins [44]. This mechanistic distinction confers activity against FKS-mutant strains that are resistant to echinocandins [45]. In the ongoing Phase III CARES study, interim analyses demonstrated complete or partial response in 66.6% (8/12) of patients with C. auris invasive candidiasis [46].

Fosmanogepix (FMGX), a first-in-class Gwt-1 inhibitor that disrupts GPI-anchored wall transfer protein-1, has demonstrated remarkable potency against MDR and pandrug-resistant C. auris isolates [47]. In an international surveillance program, manogepix (the active moiety) exhibited MIC50/90 values of 0.004–0.008 μg/mL against pandrug-resistant strains [48, 49]. A Phase II trial reported 89% (8/9) 30-day survival in patients with MDR C. auris candidemia [48]. The agent’s dual intravenous and oral formulations, combined with adequate cerebrospinal fluid and intravitreal penetration in rabbit models, position it as a versatile option for disseminated infections. Olorofim, an orotomide inhibiting fungal dihydroorotate dehydrogenase, has completed Phase IIb studies and met its primary endpoint in the Phase III OASIS trial for invasive aspergillosis, with activity extending to C. auris [50].

Novel Compounds: Exploiting Underexploited Targets

Beyond the clinical pipeline, structurally unique compounds have emerged from natural product discovery and rational design, targeting fungal cell wall components. Coniotins A-D, lipopetaibiotics isolated from Coniochaeta hoffmannii through a prefractionated library screening platform, represent a class of antifungal agents [51]. Coniotin A exhibits potent activity against MDR C. auris (MIC 4 μg/mL) with minimal hemolytic and cytotoxic profiles. Notably, it demonstrates ultra-strong synergy with caspofungin, reducing the caspofungin MIC against refractory C. auris to the CLSI breakpoint of 2 μg/mL. In a C. elegans infection model, coniotin A extended the lifespan of animals infected with caspofungin- and fluconazole-resistant C. auris by approximately 30% over two days. The identification of its hybrid PKS-NRPS biosynthetic gene cluster-encoding three NRPSs comprising 21 modules corresponding precisely to the amino acid residues-provides a genetic framework for analog development [52].

Gua-SMACS-16, a cationic supramolecule featuring a polyhedral oligomeric silsesquioxane core with 16 peripheral guanidinium groups, operates through cytoplasmic membrane disruption in a β-glucan-dependent manner. While highly selective for C. tropicalis as monotherapy, the compound exhibits ultra-strong synergy with caspofungin against all tested Candida species including C. auris [53]. The combination reduces MICs by orders of magnitude, with the fractional inhibitory concentration index falling below 0.034-well below the ≤0.05 benchmark for ultrasynergy [54]. Mechanistically, caspofungin-mediated reduction in cell wall β-glucan permits enhanced Gua-SMACS-16 diffusion to the cytoplasmic membrane, while membrane disruption may impair the membrane-bound 1,3-β-glucan synthase, rendering cells more susceptible to both agents [25].

Peptide-Based Therapies: Anti-Virulence Strategies

The bacterial peptide EntV, derived from Enterococcus faecalis, exemplifies an alternative paradigm-anti-virulence rather than direct fungicidal activity. The 12-amino acid α7 helix of this peptide retains full activity by inhibiting hyphal morphogenesis and biofilm formation, thereby attenuating pathogenicity without exerting selective pressure for resistance. Through synthetic molecular evolution, researchers generated a combinatorial library from the 10-amino acid variant and identified gain-of-function peptides with activity comparable to the 12-amino acid parent. Chemical modifications-including D-amino acid substitutions and hydrocarbon stapling-substantially improved proteolytic stability, with the stapled variant exhibiting approximately 60% remaining peptide after 24 h in human serum (estimated half-life of 33 h) compared to 10% for the unmodified peptide [55]. In murine models of oropharyngeal and systemic candidiasis, these engineered peptides significantly reduced fungal burden and epithelial invasion. Notably, P4 demonstrated efficacy against C. auris and Cryptococcus species, suggesting broad-spectrum potential [56].

Nanoparticle Delivery Systems: Overcoming Biofilm Barriers

Nanoparticle-based strategies address the formidable challenge of C. auris biofilm-associated infections, where the extracellular matrix impedes drug penetration and shields resident cells. Amphotericin B-loaded nanoemulsions (NEA) with approximately 40 nm droplet size showed superior antibiofilm activity compared to free amphotericin B, reducing biofilm viability to 17% at 0.19 μg/mL versus 93–100% for free drug at equivalent concentrations [57].

Metallic nanoparticles offer multiple mechanisms of action. Silver nanoparticles (AgNPs) may disrupt biofilm cellular integrity through silver ion release and reactive oxygen species (ROS) generation, with 1–3 nm particles eradicating preformed C. auris biofilms at IC50 of 0.48 ppm. Surface coatings functionalized with AgNPs prevent biofilm formation by inhibiting initial cell adhesion [58]. Zinc oxide nanoparticles could downregulate the adhesion gene ALS5 by 7.2-fold, interfering with cell adhesion and biofilm development [56]. Bismuth nanoparticles, notable for their relatively low toxicity compared to other heavy metals, exhibit antibiofilm activity with IC50 values ranging from 5.1 to 113.1 μg/mL across four clades, disrupting cell morphology and overall biofilm architecture [59].

Vaccines: Immunoprophylaxis Against MDR C. auris

The β-glucan chitosan particle (GCP) vaccine represents a paradigm-shifting approach-a standalone immunoprophylactic strategy leveraging the conserved fungal cell wall architecture. Mechanistic studies revealed that anti-GCP antibodies target N-linked and O-linked glycans of cell wall glycoproteins, with reactivity substantially diminished following PNGase F deglycosylation and completely abrogated by alkaline treatment [60].

Vaccinated mice exhibited significantly reduced fungal burden in kidneys, heart, and brain, with fewer and smaller fungal lesions and preserved tissue architecture. Passive transfer of anti-GCP sera and CD4+ T-cell depletion studies confirmed that both humoral immunity and CD4+ T helper cells are essential for protection. The Th2/Th17-polarized response (IL-4- and IL-17-producing T cells) induced by GCP contrasts with the pathogenic Th1 bias observed in C. auris skin infection, potentially explaining its protective efficacy [61].

Conclusion

In summary, the multidrug resistance of C. auris is driven through a complex network of genetic mutations and metabolic reprogramming, and phenotypic plasticity. Despite the advancements in decoding these resistance networks, the clinical reality of managing multidrug-resistant C. auris infections remains incredibly challenging. In the future, overcoming the global public health crisis precipitated by C. auris, it needs a highly integrated, cross-disciplinary approach that unites molecular mycology, clinical infectious diseases, advanced pharmacokinetics, and materials science.

Author Contribution

Fenglin Shao, Tingru Wu and Jingjing Su wrote the main manuscript text and Fenglin Shao prepared Fig. 1. All authors reviewed the manuscript.

Funding

This work was not supported by any funding.

Data Availability

No datasets were generated or analysed during the current study.

Declarations

Conflict of interest

The authors declare no conflict of interest.