phaidra.vetmeduni.ac.at o:2069 DOI 10.1128/mbio.00799-22 Transcriptomics and Phenotyping Define Genetic Signatures Associated with Echinocandin Resistance in Candida auris Candida auris emerged as a human fungal pathogen only during the past decade. Remarkably, C. auris displays high degrees of genomic diversity and phenotypic plasticity, with four major clades causing hospital outbreaks with high mortality and morbidity rates. C. auris can show clinical resistance to all classes of antifungal drugs, including echinocandins that are usually recommended as first-line therapies for invasive candidiasis. Here, we exploit transcriptomics coupled with phenotypic profiling to characterize a set of clinical C. auris isolates displaying pronounced echinocandin resistance (ECN-R). A hot spot mutation in the echinocandin FKS1 target gene is present in all resistant isolates. Moreover, ECN-R strains share a core signature set of 362 genes differentially expressed in ECN-R isolates. Among others, mitochondrial gene expression and genes affecting cell wall function appear to be the most prominent, with the latter correlating well with enhanced adhesive traits, increased cell wall mannan content, and altered sensitivity to cell wall stress of ECN-R isolates. Moreover, ECN-R phenotypic signatures were also linked to pathogen recognition and interaction with immune cells. Hence, transcriptomics paired with phenotyping is a suitable tool to predict resistance and fitness traits as well as treatment outcomes in pathogen populations with complex phenotypic diversity. IMPORTANCE 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. However, the mechanisms underlying this phenotypic diversity remain poorly understood. We identify transcriptomic signatures in C. auris isolates resistant to otherwise fungicidal echinocandins. We identify a set of differentially expressed genes shared by resistant strains compared to unrelated susceptible isolates. Moreover, phenotyping demonstrates that resistant strains show distinct behaviors, with implications for host-pathogen interactions. Hence, this work provides a solid basis to identify the mechanistic links between antifungal multidrug resistance and fitness costs that affect the interaction of C. auris with host immune defenses. eng Cell-Wall; Stress-Adaptation; Susceptibility; Identification; Disruption; Mechanisms; Evolution; Responses; Package; Strain 2023-09-05T13:14:38.256Z LOMv1.0 Author BEGIN:VCARD VERSION:3.0 N:Jenull;Sabrina; FN:Sabrina Jenull END:VCARD BEGIN:VCARD VERSION:3.0 N:Kuchler;Karl; FN:Karl Kuchler END:VCARD BEGIN:VCARD VERSION:3.0 N:Chauhan;Neeraj; FN:Neeraj Chauhan END:VCARD BEGIN:VCARD VERSION:3.0 N:Chowdhary;Anuradha; FN:Anuradha Chowdhary END:VCARD BEGIN:VCARD VERSION:3.0 N:Stoiber;Anton; FN:Anton Stoiber END:VCARD BEGIN:VCARD VERSION:3.0 N:Petryshyn;Andriy; FN:Andriy Petryshyn END:VCARD BEGIN:VCARD VERSION:3.0 N:Singh;Ashutosh; FN:Ashutosh Singh END:VCARD BEGIN:VCARD VERSION:3.0 N:Chauhan;Manju; FN:Manju Chauhan END:VCARD BEGIN:VCARD VERSION:3.0 N:Nogueira;Filomena; FN:Filomena Nogueira END:VCARD BEGIN:VCARD VERSION:3.0 N:Trinh;Phan-Canh; FN:Phan-Canh Trinh END:VCARD BEGIN:VCARD VERSION:3.0 N:Penninger;Philipp; FN:Philipp Penninger END:VCARD BEGIN:VCARD VERSION:3.0 N:Tsymala;Irina; FN:Irina Tsymala END:VCARD BEGIN:VCARD VERSION:3.0 N:Shivarathri;Raju; FN:Raju Shivarathri END:VCARD https://w3id.org/kim/hcrt/scheme https://w3id.org/kim/hcrt/text Textdokument Text LOMv1.0 yes https://creativecommons.org/licenses/by/4.0 application/pdf 597174 https://phaidra.vetmeduni.ac.at/o:2069 https://phaidra.vetmeduni.ac.at/api/object/o:2069/thumbnail LOMv1.0 discipline