Multi‐Omics Analysis of Experimentally Evolved Candida auris Isolates Reveals Modulation of Sterols, Sphingolipids, and Oxidative Stress in Acquired Amphotericin B Resistance
Year: 2025
Type: article
Abstract: ABSTRACT Clinical isolates of Candida auris show a high prevalence of resistance to Amphotericin B (AmB)—an uncommon trait in most Candida species. Alterations in ergosterol biosynthesis can contribute to acquired AmB resistance in C. auris laboratory strains but are rarely seen in clinical isolates. In this study, we experimentally evolved two drug‐susceptible Clade II isolates of C. auris to develop AmB resistance. The evolved strains displayed a four to eight fold increase in MIC50 compared to the parental cells. We analyzed changes in their karyotype, genome, lipidome, and transcriptome associated with this acquired resistance. In one lineage, AOX2 was upregulated, and its deletion reversed the AmB resistance phenotype. The aox2Δ mutant also failed to evolve AmB resistance under experimental conditions. In the same lineage, restoring the UPC2 S332R and RTG3 S101T mutations to the wild‐type allele restored AmB susceptibility. In another lineage, the ergosterol and sphingolipid pathways were observed to play a critical role, and upregulation of the ERG genes elevated the total sterol content, while significant downregulation of HSX11 (glucosylceramide synthase) resulted in lower levels of glucosylceramides. To our knowledge, this study is the first to show that AmB resistance in C. auris can be acquired through mechanisms both dependent on or independent of sterol content modulation, highlighting Aox2 and Upc2 as key regulators of amphotericin resistance.
Source: Molecular Microbiology
DOI: 10.1111/mmi.15379
Authors: Anshu Chauhan, Hans Carolus, Dimitrios Sofras, Mohit Kumar, Praveen Kumar, Remya Nair, Aswathy Narayanan, Kusum Yadav, Basharat Ali, Vladislav Biriukov, Amandeep Saini, Ian Leaves, Rudy Vergauwen, Celia Lobo Romero, Dhara Malavia‐Jones, Ashutosh Singh, Atanu Banerjee, Shivaprakash M. Rudramurthy, Arunaloke Chakrabarti, Alok K. Mondal, Naseem A. Gaur, Kaustuv Sanyal, Jeffrey M. Rybak, Toni Gabaldón, Patrick Van Dijck, Neil A. R. Gow, Rajendra Prasad
Institutions: Amity University Gurugram, KU Leuven, International Centre for Genetic Engineering and Biotechnology, Winship Cancer Institute, Jawaharlal Nehru Centre for Advanced Scientific Research, Jawaharlal Nehru University, Barcelona Supercomputing Center, Institute for Research in Biomedicine, Barcelona Institute of Science and Technology, MRC Centre for Medical Mycology, University of Lucknow, Post Graduate Institute of Medical Education and Research, St. Jude Children's Research Hospital, Institució Catalana de Recerca i Estudis Avançats, Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red, Centro de Investigación Biomédica en Red Enfermedades Infecciosas
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Funders: Gordon and Betty Moore Foundation, European Molecular Biology Organization, Fundació la Marató de TV3, Wellcome Trust, “la Caixa” Foundation, Joint Programming Initiative on Antimicrobial Resistance, European Commission, Department of Biotechnology, Ministry of Science and Technology, India, Indian Council of Medical Research, Council of Scientific and Industrial Research, India, Amity University, Fonds Wetenschappelijk Onderzoek, KU Leuven, Ministerio de Ciencia e Innovación, Jawaharlal Nehru Centre for Advanced Scientific Research, Vlaamse regering, Medical Research Council Centre for Medical Mycology, Medical Research Council, Agència de Gestió d'Ajuts Universitaris i de Recerca, European Regional Development Fund, Amity Institute of Biotechnology, Amity University
Awards: G1036004506, G1046215618, G1276714150, G1408940860, G1620553015, G1666550810, Disrupting drug resistance by exploiting collateral sensitivity to design novel therapeutic strategies for C. auris and C. glabrata infections (CycleDrug)., G2085528529, MRC Centre for Medical Mycology, G2659495742, G2669277958, G2913433471, Targeting a new kingdom: the nature and significance of Type VI secretion system-mediated anti-fungal activity, G3544722760, G3607896745, G434337789, G4469042973, Making and breaking the cell walls of fungal pathogens., G4824533134, G4887036848, From ‘molecular pattern’ to ligand structure and function – the origins of antifungal immunity, G517780428, IMPACT OF FUNGAL ADAPTATION UPON HOST RECOGNITION AND PATHOGENESIS, G558631938, G6585760861, Experimental evolution in Candida biofilms: does drug tolerance facilitate drug resistance development in fungi?, G6855924992, Deciphering the Origin of the Eukaryotic Cell, G7967901672, Genetic and chemical validation of sugar nucleotide biosynthesis as a target against Candida albicans, G8451058061
OpenAlex ID: W4411077968