Suchergebnisse

Fungal pathogens pose an increasingly worrying threat to human health, food security and ecosystem diversity. To tackle fungal infections and improve current diagnostic and therapeutic tools it is necessary to understand virulence and antifungal drug resistance mechanisms in diverse species. Recent advances in genomics approaches have provided a suitable framework to understand these phenotypes, which ultimately depend on genetically encoded determinants. In this work, we review how the study of genome sequences has been key to ascertain the bases of virulence and drug resistance traits. We focus on the contribution of comparative genomics, population genomics and directed evolution studies. In addition, we discuss how different types of genomic mutations (small or structural variants) contribute to intraspecific differences in virulence or drug resistance. Finally, we review current challenges in the field and anticipate future directions to solve them. In summary, this work provides a short overview of how genomics can be used to understand virulence and drug resistance in fungal pathogens. ; TG group acknowledges support from the Spanish Ministry of Science and Innovation for grant PGC2018-099921-B-I00, cofounded by European Regional Development Fund (ERDF); from the Catalan Research Agency (AGAUR) SGR423; from the European Union's Horizon 2020 research and innovation programme (ERC-2016-724173); from the Gordon and Betty Moore Foundation (Grant GBMF9742); from the 'La Caixa' foundation (Grant LCF/PR/HR21/00737), and from the Instituto de Salud Carlos III (INB Grant PT17/0009/0023 and CIBERINFEC CB21/13/00061- ISCIII-SGEFI/ERDF). MAST received a predoctoral fellowship from the 'Caixa' Foundation (LCF/BQ/DR19/11740023). ; Peer Reviewed ; Postprint (published version)

Oxidative phosphorylation is among the most conserved mitochondrial pathways. However, one of the cornerstones of this pathway, the multi-protein complex NADH : ubiquinone oxidoreductase (complex I) has been lost multiple independent times in diverse eukaryotic lineages. The causes and consequences of these convergent losses remain poorly understood. Here, we used a comparative genomics approach to reconstruct evolutionary paths leading to complex I loss and infer possible evolutionary scenarios. By mining available mitochondrial and nuclear genomes, we identified eight independent events of mitochondrial complex I loss across eukaryotes, of which six occurred in fungal lineages. We focused on three recent loss events that affect closely related fungal species, and inferred genomic changes convergently associated with complex I loss. Based on these results, we predict novel complex I functional partners and relate the loss of complex I with the presence of increased mitochondrial antioxidants, higher fermentative capabilities, duplications of alternative dehydrogenases, loss of alternative oxidases and adaptation to antifungal compounds. To explain these findings, we hypothesize that a combination of previously acquired compensatory mechanisms and exposure to environmental triggers of oxidative stress (such as hypoxia and/or toxic chemicals) induced complex I loss in fungi. ; This work was supported by grants from the Spanish Ministry of Science and Innovation (grant no. PGC2018-099921-B-I00), cofounded by European Regional Development Fund (ERDF); from the CERCA Programme/Generalitat de Catalunya; from the Catalan Research Agency (AGAUR) SGR423; from the European Union's Horizon 2020 research and (grant no. ERC-2016-724173); and from the Instituto de Salud Carlos III—Instituto Nacional de Bioinformatica, (grant no. PT17/0009/0023—ISCIII-SGEFI/ERDF). M.À.S.-T. received a Predoctoral Each Fellowship from 'Caixa' Foundation (grant no. LCF/BQ/DR19/11740023). ; Peer Reviewed ; Postprint (published version)

Fungal infections are a growing medical concern, in part due to increased resistance to one or multiple antifungal drugs. However, the evolutionary processes underpinning the acquisition of antifungal drug resistance are poorly understood. Here, we used experimental microevolution to study the adaptation of the yeast pathogen Candida glabrata to fluconazole and anidulafungin, two widely used antifungal drugs with different modes of action. Our results show widespread ability of rapid adaptation to one or both drugs. Resistance, including multidrug resistance, is often acquired at moderate fitness costs and mediated by mutations in a limited set of genes that are recurrently and specifically mutated in strains adapted to each of the drugs. Importantly, we uncover a dual role of ERG3 mutations in resistance to anidulafungin and cross-resistance to fluconazole in a subset of anidulafungin-adapted strains. Our results shed light on the mutational paths leading to resistance and cross-resistance to antifungal drugs. ; The authors thank Ester Saus, Jesse Willis, and Cinta Pegueroles for their help and technical assistance with some of the analyses. M.A.S.-T. received a predoctoral fellowship from the ''Caixa'' Foundation (LCF/BQ/DR19/11740023). The T.G. group acknowledges support from the Spanish Ministry of Science and Innovation grant no. PGC2018-099921-B-I00, cofounded by the European Regional Development Fund (ERDF); from the CERCA Programme/Generalitat de Catalunya; from the Catalan Research Agency (AGAUR) SGR423; the European Union's Horizon 2020 research and innovation program under grant agreement no. ERC-2016-724173; and the Marie Sk1odowska-Curie grant agreement no. H2020-MSCA-IF-2017-793699. The group also receives support from an INB grant (PT17/0009/0023-ISCIII-SGEFI/ERDF). The Bioactive Microbial Metabolites research platform (BiMM) is supported by grants K3- G-2/026-2013 and COMBIS/ LS16005, both funded by the Lower Austria Science and Education Fund (NfB). ; Peer Reviewed ; Postprint (published version)