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Aneuploidy and Acquired Antifungal Drug Resistance in Candida species

念珠菌属的非整倍性和获得性抗真菌药物耐药性

基本信息

批准号：
10062478
负责人：
Anna M. Selmecki
金额：
$ 45.48万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-12-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10062478
关键词：
Aneuploidy Antifungal Agents Automobile Driving Azole resistance Azoles Bioinformatics Candida Candida albicans Candida albicans resistance Candida auris Cells Chromosome Arm Chromosome abnormality Chromosomes Clinical Cryptococcus neoformans DNA Repair Gene DNA Sequence Development Drug Exposure Drug resistance Elements Engineering Event Evolution Exhibits Exposure to Failure Flow Cytometry Fluconazole Fluconazole resistance Frequencies Fungal Drug Resistance Future Gene Amplification Generations Genes Genetic Recombination Genome Genomics Goals Hospitals Human In Vitro Infection Inverted Repeat Sequences Investigation Isochromosomes Karyotype Lead Left Measures Molecular Molecular Genetics Morbidity - disease rate Multi-Drug Resistance Mutation Outcome Outcome Study Pharmaceutical Preparations Pharmacotherapy Point Mutation Population Positioning Attribute Predisposition Recurrence Repetitive Sequence Reporter Reproducibility Research Research Project Grants Resistance Resistant candida Sepsis Stress Structure System TAC1 gene Techniques Testing Therapeutic Time Work antimicrobial arm base comparative genomics digital experience experimental study fitness genetic approach genome sequencing in vivo interdisciplinary approach mathematical model mortality mouse model neglect novel novel strategies novel therapeutic intervention pathogenic fungus resistance gene resistance mechanism resistance mutation theories whole genome yeast genetics

项目摘要

ABSTRACT The rapid emergence of antifungal drug resistance in Candida species poses a severe antimicrobial threat worldwide. Azole antifungals, especially fluconazole, are widely used for treating Candida infections, however, azoles induce genome changes in diverse Candida species and acquired resistance can rapidly emerge. Despite this, we lack a comprehensive understanding of the molecular events that drive the acquisition of azole resistance in real time. Previously, we identified that 50% of fluconazole resistant Candida albicans clinical isolates are aneuploid and some of these aneuploidies cause pan-azole resistance. More recently, aneuploidy- acquired fluconazole resistance has been observed in many diverse human fungal pathogens, yet despite the frequency of these aneuploid events, the mechanism causing them is not known. We have developed cutting- edge multidisciplinary approaches that uniquely position us to define the rate and mechanisms of acquired azole resistance in a rigorous and reproducible way. These approaches include controlled in vitro and in vivo evolution, comprehensive comparative genomics and bioinformatics techniques, and extensive molecular genetic approaches. The aims of this application take a new approach to identifying the mechanisms driving antifungal drug resistance. In aim 1, we will determine the impact of azole stress on the rate and dynamics of acquired azole resistance. This will simultaneously enable us to identify novel and recurrent mechanisms of azole resistance, aneuploidy-derived resistance mechanisms, and the extent to which these mutations cause pan- azole and multi-drug resistance. In aim 2, the frequency of segmental chromosome aneuploidies known to cause resistance across diverse clinical isolates will be determined both in vitro and in vivo. Additionally, the impact of repetitive DNA sequences and DNA repair proteins on the formation of segmental aneuploidies will be determined. Our work is significant because it will identify the frequency, order and trajectory of mutations as they arise in a population and how these mutations cause antifungal drug resistance. Together the outcomes from these studies will identify the mechanisms that underlie how C. albicans acquires resistance and can pave the way for developing therapeutics to reduce the significant morbidity and mortality caused by diverse antifungal drug resistant Candida species.

摘要