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Candida auris is an emerging healthcare-associated pathogen of global concern. Recent reports have identified C. auris isolates that grow in cellular aggregates or filaments, often without a clear genetic explanation. To investigate the regulation of C. auris morphogenesis, we applied an Agrobacterium -mediated transformation system to all four C. auris clades. We identified aggregating mutants associated with disruption of chitin regulation, while disruption of ELM1 produced a polarized, filamentous growth morphology. We developed a transiently expressed Cas9 and sgRNA system for C. auris that significantly increased targeted transformation efficiency across the four C. auris clades. Using this system, we confirmed the roles of C. auris morphogenesis regulators. Morphogenic mutants showed dysregulated chitinase expression, attenuated virulence, and altered antifungal susceptibility. Our findings provide insights into the genetic regulation of aggregating and filamentous morphogenesis in C. auris . Furthermore, the genetic tools described here will allow for efficient manipulation of the C. auris genome. Some isolates of the emerging fungal pathogen Candida auris can form cellular aggregates or filaments. Here, Santana and O’Meara use Agrobacterium -mediated transformation and a CRISPR-Cas9 system to identify several genes that regulate C. auris morphogenesis.

Antimicrobial resistance is a public health threat associated with increased morbidity, mortality and financial burden in nursing homes and other healthcare settings 1 . Residents of nursing homes are at increased risk of pathogen colonization and infection owing to antimicrobial-resistant bacteria and fungi. Nursing homes act as reservoirs, amplifiers and disseminators of antimicrobial resistance in healthcare networks and across geographical regions 2 . Here we investigate the genomic epidemiology of the emerging, multidrug-resistant human fungal pathogen Candida auris in a ventilator-capable nursing home. Coupling strain-resolved metagenomics with isolate sequencing, we report skin colonization and clonal spread of C.   auris on the skin of nursing home residents and throughout a metropolitan region. We also report that most Enterococcus faecium , Staphylococcus aureus , Klebsiella pneumoniae , Acinetobacter baumannii , Pseudomonas aeruginosa and Entobacter species (ESKAPE) pathogens and other high-priority pathogens (including Escherichia coli , Providencia stuartii , Proteus mirabilis and Morganella morganii ) are shared in a nursing home. Integrating microbiome and clinical microbiology data, we detect carbapenemase genes at multiple skin sites on residents identified as carriers of these genes. We analyse publicly available shotgun metagenomic samples (stool and skin) collected from residents with varying medical conditions living in seven other nursing homes and provide additional evidence of previously unappreciated bacterial strain sharing. Taken together, our data suggest that skin is a reservoir for colonization by C.   auris and ESKAPE pathogens and their associated antimicrobial-resistance genes. Analyses of strain-resolved metagenomics with isolate sequencing data of skin samples from residents at nursing homes suggest that skin is a reservoir for Candida auris and other multidrug-resistant bacterial species.

Candida auris is an emerging nosocomial fungal pathogen associated with life-threatening invasive disease due to its persistent colonization, high level of transmissibility and multi-drug resistance. Aggregative and non-aggregative growth phenotypes for C. auris strains with different biofilm forming abilities, drug susceptibilities and virulence characteristics have been described. Using comprehensive transcriptional analysis we identified key cell surface adhesins that were highly upregulated in the aggregative phenotype during in vitro and in vivo grown biofilms using a mouse model of catheter infection. Phenotypic and functional evaluations of generated null mutants demonstrated crucial roles for the adhesins Als4112 and Scf1 in mediating cell-cell adherence, coaggregation and biofilm formation. While individual mutants were largely non-aggregative, in combination cells were able to co-adhere and aggregate, as directly demonstrated by measuring cell adhesion forces using single-cell atomic force spectroscopy. This co-adherence indicates their role as complementary adhesins, which despite their limited similarity, may function redundantly to promote cell-cell interaction and biofilm formation. Functional diversity of cell wall proteins may be a form of regulation that provides the aggregative phenotype of C. auris with flexibility and rapid adaptation to the environment, potentially impacting persistence and virulence. Here, Wang et al show that Candida auris cell wall adhesins function redundantly to promote cell-cell interaction and biofilm formation as a form of regulation and potential adaption to the environment.

Invasive candidiasis affects 1.6 million people annually, with high mortality among immunocompromised and hospitalized patients. Echinocandins are frontline antifungals, but rising resistance limits their efficacy. Here, we show that Candida albicans and multidrug-resistant Candida auris share a conserved cell wall architecture yet differ markedly in their adaptive responses to echinocandins. Solid-state NMR reveals that both species possess a rigid inner layer of tightly associated chitin microfibrils and β−1,3-glucans, supported by a flexible matrix of β−1,6-glucans and additional β−1,3-glucans. Outer mannan fibrils rely on α−1,2-linked sidechains to maintain contact with the inner wall. In both species, caspofungin rigidifies β−1,6-glucans and mannan sidechains and reduces water permeability during β−1,3-glucan depletion; however, C. albicans undergoes wall thickening and alterations in chitin and glucan dynamics, whereas C. auris maintains integrity through β−1,6-glucan upregulation. Deletion of KRE6a , which encodes β−1,6-glucan synthase, reduces echinocandin susceptibility in C. auris , further highlighting β−1,6-glucan’s critical role in adaptive remodeling. The prevalent fungal pathogen, Candida albicans , and the emerging multidrug-resistant superfungus, Candida auris , share the same initial cell wall architecture but remodel it differently in response to echinocandin-induced antifungal stress.

The rise of drug-resistant fungal species, such as Candida auris , poses a serious threat to global health, with mortality rates exceeding 40% and resistance rates surpassing 90%. The limited arsenal of effective antifungal agents underscores the urgent need for novel strategies. Here, we systematically evaluate the role of histone H3 post-translational modifications in C. auris drug resistance, focusing on acetylation mediated by Gcn5 and Rtt109, and methylation mediated by Set1, Set2, and Dot1. Mutants deficient in these enzymes exhibit varying degrees of antifungal drug sensitivity. Notably, we discover that GCN5 depletion and the subsequent loss of histone H3 acetylation downregulates key genes involved in ergosterol biosynthesis and drug efflux, resulting in increased susceptibility to azoles and polyenes. Additionally, Gcn5 regulates cell wall integrity and echinocandin resistance through the calcineurin signaling pathway and transcription factor Cas5. In infection models using Galleria mellonella and immunocompromised mice, GCN5 deletion significantly reduces the virulence of C. auris . Furthermore, the Gcn5 inhibitor CPTH 2 synergizes with caspofungin in vitro and in vivo without notable toxicity. These findings highlight the critical role of Gcn5 in the resistance and pathogenicity of C. auris , positioning it as a promising therapeutic target for combating invasive fungal infections. In this work, authors show that the key epigenetic regulator Gcn5 contributes to multidrug resistance in Candida auris . The inhibition of its activity by CPTH 2 synergizes with caspofungin, presenting a promising antifungal strategy.

Candida auris , an emerging fungal pathogen characterized by its multidrug resistance and high mortality rates, poses a significant public health challenge. Despite its importance, the signaling pathways governing virulence and antifungal resistance in C. auris remain poorly understood. This study investigates the calcineurin pathway in C. auris , critical for virulence and antifungal resistance in other fungal pathogens. Calcineurin, a calcium/calmodulin-dependent protein phosphatase, comprises a catalytic subunit (Cna1) and a regulatory subunit (Cnb1) in C. auris . Our findings reveal that deletion of CNA1 or CNB1 disrupts extreme thermotolerance and cell membrane and wall integrity, leading to increased susceptibility to azoles and echinocandins. Moreover, we identified a downstream transcription factor, Crz1, which plays a central role in this pathway in other fungal species. Deletion of CRZ1 resulted in thermotolerance and membrane integrity defects comparable to those of cna1 Δ and cnb1 Δ mutants, along with increased azole susceptibility. Supporting it, fluconazole treatment induced Crz1 nuclear translocation in a Cna1-dependent manner. However, unlike cna1 Δ and cnb1 Δ mutants, the crz1 Δ mutant displayed increased resistance to echinocandins, suggesting the opposing roles for Crz1 in regulating cell wall integrity. Nevertheless, echinocandins also promoted Crz1 nuclear translocation via Cna1, underscoring the complex regulatory mechanisms at play. Cna1 was found to be required for virulence in both the Drosophila systemic infection model and the murine skin infection model. However, in a systemic murine infection model, both calcineurin and Crz1 appeared dispensable for C. auris virulence. Our findings highlight that the evolutionarily conserved calcineurin pathway employs distinct regulatory mechanisms to perform divergent roles in regulating extreme thermotolerance, cell wall and membrane integrity, antifungal drug resistance, and virulence in C. auris .

Candida auris is a fungal pathogen notorious for persistent skin colonization and transmission in healthcare settings. Here, we show that a C. auris conserved adhesin, Als4112, is required for skin colonization via keratinocyte attachment and direct interactions with host extracellular matrix proteins, especially basement membrane proteins such as laminin. Deletion of ALS4112 reduces skin colonization in mouse models of epicutaneous and systemic infection. In addition, coating plastic and catheter surfaces with collagen I or III inhibits C. auris attachment and biofilm formation. Our study highlights the critical role of Als4112 in C. auris colonization and virulence, and explores potential strategies to reduce the pathogen’s adherence to abiotic surfaces and thus its spread in healthcare settings. Candida auris is a fungal pathogen notorious for persistent skin colonization and transmission in healthcare settings. Here, Zhao et al. explore the mechanisms driving pathogen’s adherence to skin, involving a conserved adhesin, as well as the potential of collagen coatings as a strategy to reduce C. auris adherence to abiotic surfaces.

The drug-resistant pathogenic yeast Candidozyma auris (formerly named Candida auris) is considered a critical health problem of global importance. As the cell wall plays a crucial role in pathobiology, here we performed a detailed bioinformatic analysis of its biosynthesis in C. auris and related Candidozyma haemuli complex species using Candida albicans and Saccharomyces cerevisiae as references. Our data indicate that the cell wall architecture described for these reference yeasts is largely conserved in Candidozyma spp.; however, expansions or reductions in gene families point to subtle alterations, particularly with respect to β­-1,3-­glucan synthesis and remodeling, phosphomannosylation, β-mannosylation, and glycosylphosphatidylinositol (GPI) proteins. In several aspects, C. auris holds a position in between C. albicans and S. cerevisiae, consistent with being classified in a separate genus. Strikingly, among the identified putative GPI proteins in C. auris are adhesins typical for both Candida (Als and Hyr/Iff) and Saccharomyces (Flo11 and Flo5-like flocculins). Further, 26 putative C. auris GPI proteins lack homologs in Candida genus species. Phenotypic analysis of one such gene, QG37_05701, showed mild phenotypes implicating a role associated with cell wall β-1,3-glucan. Altogether, our study uncovered a wealth of information relevant for the pathogenicity of C. auris as well as targets for follow-up studies. A comparative genomic analysis of cell wall synthesis in the pathogenic yeast C. auris.

Candida auris is an emerging multidrug-resistant yeast that causes healthcare-associated and deep-seated infections. Notably, the emergence of this yeast is alarming as it exhibits resistance to azoles, echinocandins, and amphotericin B, which may lead to clinical treatment failure in patients. This study aims to identify and characterize the genetic determinants of antifungal resistance in C. auris among some local clinical isolates to contribute for understanding the molecular epidemiology of C. auris in Egypt. Four test strains were identified based on the ribosomal internal transcribed spacer (ITS) region sequence and phylogenetic analysis. Antifungal susceptibility was determined using the VITEK 2 system. Molecular analysis of ERG11 , ERG3 , FKS1 , and FKS2 was used to identify mutations associated with antifungal resistance. The four test strains were identified as C. auris . Evolutionary analysis was conducted, and sequences of ITS regions were submitted to GenBank. The mutations Y132F in ERG11 and F635Y in FKS2 were identified, which are known to confer resistance to azoles and echinocandins, respectively. The emergence of C. auris in Egypt represents a public health concern. Hospitals should implement strict infection control measures to prevent its spread. Effective treatment guidelines and ongoing monitoring of antifungal resistance are essential to combat this emerging pathogen.

is an emerging multidrug-resistant fungal pathogen that poses a significant global health threat. Since its discovery in 2009, has rapidly spread worldwide, causing severe infections with high mortality rates, particularly in healthcare settings. Its ability to persist in the environment, form biofilms, and resist multiple antifungal drugs underscores the urgent need to understand its pathogenicity mechanisms and associated signaling pathways. Such insights are crucial for elucidating its unique virulence traits and developing targeted therapeutic strategies. Current studies have identified several key pathways involved in its pathogenicity and antifungal drug resistance. The Ras/cAMP/PKA pathway regulates critical virulence factors, including thermotolerance, morphological plasticity, and biofilm formation. The mitogen-activated protein kinase (MAPK) and calcineurin pathways contribute to stress responses and antifungal drug resistance. The regulation of Ace2 and morphogenesis (RAM) pathway influences cell aggregation, while the target of rapamycin (TOR) pathway affects filamentous growth and biofilm development. However, the distinct characteristics of , such as its rapid environmental spread and clade-specific traits, warrant further investigation into additional signaling pathways. This review provides a comprehensive analysis of known signaling pathways associated with pathogenicity and antifungal drug resistance, integrating insights from other fungal pathogens. By synthesizing current knowledge and identifying research gaps, this review offers new perspectives on future research directions and potential therapeutic targets against this formidable pathogen.