Candida auris is an emerging multidrug-resistant human fungal pathogen refractory to treatment by several classes of antifungal drugs. Unlike other Candida species, C. auris can adhere to human skin for prolonged periods of time, allowing for efficient skin-to-skin transmission in the hospital environments. However, molecular mechanisms underlying pronounced multidrug resistance and adhesion traits are poorly understood. Two-component signal transduction and mitogen-activated protein (MAP) kinase signaling are important regulators of adherence, antifungal drug resistance, and virulence. Here, we report that genetic removal of SSK1 encoding a response regulator and the mitogen-associated protein kinase HOG1 restores the susceptibility to both amphotericin B (AMB) and caspofungin (CAS) in C. auris clinical strains. The loss of SSK1 and HOG1 alters membrane lipid permeability, cell wall mannan content, and hyperresistance to cell wall-perturbing agents. Interestingly, our data reveal variable functions of SSK1 and HOG1 in different C. auris clinical isolates, suggesting a pronounced genetic plasticity affecting cell wall function, stress adaptation, and multidrug resistance. Taken together, our data suggest that targeting two-component signal transduction systems could be suitable for restoring C. auris susceptibility to antifungal drugs.
IMPORTANCE Candida auris is an emerging multidrug-resistant (MDR) fungal pathogen that presents a serious global threat to human health. The Centers for Disease Control and Prevention (CDC) have classified C. auris as an urgent threat to public health for the next decade due to its major clinical and economic impact and the lack of effective antifungal drugs and because of future projections concerning new C. auris infections. Importantly, the Global Antimicrobial Resistance Surveillance System (GLASS) has highlighted the need for more robust and efficacious global surveillance schemes enabling the identification and monitoring of antifungal resistance in Candida infections. Despite the clinical relevance of C. auris infections, our overall understanding of its pathophysiology and virulence, its response to human immune surveillance, and the molecular basis of multiple antifungal resistance remains in its infancy. Here, we show a marked phenotypic plasticity of C. auris clinical isolates. Further, we demonstrate critical roles of stress response mechanisms in regulating multidrug resistance and show that cell wall architecture and composition are key elements that determine antifungal drug susceptibilities. Our data promise new therapeutic options to treat drug-refractory C. auris infections.
Health care facilities are facing serious threats by the recently emerging human fungal pathogen Candida auris owing to its pronounced antifungal multidrug resistance and poor diagnostic tools. Distinct C. auris clades evolved seemingly simultaneously at independent geographical locations and display both genetic and phenotypic diversity. Although comparative genomics and phenotypic profiling studies are increasing, we still lack mechanistic knowledge about the C. auris species diversification and clinical heterogeneity. Since gene expression variability impacts phenotypic plasticity, we aimed to characterize transcriptomic signatures of C. auris patient isolates with distinct antifungal susceptibility profiles in this study. First, we employed an antifungal susceptibility screening of clinical C. auris isolates to identify divergent intra-clade responses to antifungal treatments. Interestingly, comparative transcriptional profiling reveals large gene expression differences between clade I isolates and one clade II strain, irrespective of their antifungal susceptibilities. However, comparisons at the clade levels demonstrate that minor changes in gene expression suffice to drive divergent drug responses. Finally, we functionally validate transcriptional signatures reflecting phenotypic divergence of clinical isolates. Thus, our results suggest that large-scale transcriptional profiling allows for predicting phenotypic diversities of patient isolates, which may help choosing suitable antifungal therapies of multidrug-resistant C. auris.
The surge in antimicrobial drug resistance in some bacterial and fungal pathogens constitutes a significant challenge to health care facilities. The emerging human fungal pathogen
Candida auris
has been particularly concerning, as isolates can display pan-antifungal resistance traits against all drugs, including echinocandins.
Candida auris
is an emerging multidrug-resistant human fungal pathogen often refractory to treatment by all classes of antifungal drugs. Amphotericin B (AmB) is a fungicidal drug that, despite its toxic side effects, remains a drug of choice for the treatment of drug-resistant fungal infections, including those caused by
C. auris
.
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