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A new pathway for azole resistance in Aspergillus fumigatus

烟曲霉唑类抗性的新途径

基本信息

批准号：
8972533
负责人：
W Scott Moye-Rowley
金额：
$ 22.48万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-06-15 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8972533
关键词：
ATP-Binding Cassette Transporters Acute Alleles Allergic Amino Acid Sequence Antifungal Agents Appearance Aspergillosis Aspergillus fumigatus Azole resistance Azoles Candida Cell membrane Cells Chemistry Chronic Clinic Clinical Code Country Data Development Disease Drug Efflux Drug Tolerance Drug effect disorder Drug resistance Elements Europe Gene Duplication Genes Genetic Genetic Screening Genetic Transcription Goals Health Healthcare Systems Human Hypersensitivity In Vitro Incidence Individual Infection Laboratories Lanosterol Lesion Link Malaria Molecular Mutagenesis Mutation Mycoses Natural regeneration Netherlands Oral Organism Pathway interactions Patients Pharmaceutical Preparations Phenotype Play Population Populations at Risk Promoter Regions Proteins Relative (related person)Reporting Research Resistance Role Route Site Survival Rate System Testing Time Trans-Activators Tuberculosis United Kingdom United States Work antimicrobial drug base clinically relevant cost effective therapy genetic analysis interest intravenous administration mortality mutant overexpression pathogen promoter research study resistance mechanism

项目摘要

DESCRIPTION (provided by applicant): Invasive Aspergillosis caused by azole resistant A. fumigatus has an alarming 12% survivability making this a clinical problem of acute significance. Early work on azole resistant isolates of A. fumigatus suggested that azole resistance was a relatively rare occurrence and that the genetic basis of resistance was most often due to changes in a gene (cyp51A) encoding the azole target protein, lanosterol α-14 demethylase. Extensive studies from a group in the Netherlands provided compelling evidence that in that country, most azole resistant A. fumigatus isolates contained a single compound mutation consisting of a duplicated region of the cyp51A promoter region (TR34) and a change in the coding sequence altering the amino acid sequence of the protein (L98H). However, more recent studies from a group in the United Kingdom indicated that alterations in the cyp51A gene were unlikely to explain all azole resistance in A. fumigatus. More than 50% of azole resistant isolates from UK patients have wild-type versions of cyp51A, inconsistent with changes at this gene explaining drug tolerance. In 2013, the UK group identified an ATP-binding cassette (ABC) transporter-encoding gene called cdr1B as being associated with azole resistance in several patient isolates. Expression of cdr1B was elevated in highly azole tolerant clinical isolates while the cyp51A remained wild-type in sequence. Overexpression of ABC transporter-encoding genes resulting in azole tolerance has been the predominant route of azole resistance in the Candida species and we believe this will emerge as a key feature of drug resistance in A. fumigatus. This application will focus on the contributions of the cdr1B gene as expression of this ABC transporter is elevated in azole resistance isolates and loss of cdr1B produces an azole sensitive phenotype. We will directly compare the azole resistance phenotypes of wild-type and cdr1BΔ cells containing various cyp51A mutations that are associated with clinically relevant drug resistance. We will also evaluate expression of cyp51A using immunological probes to determine if these mutant alleles influence protein levels; information that is currently unavailable in A. fumigatus. We will carry out a forward genetic screen using impala transposon mutagenesis to identify genes that modulate cdr1B expression. Together, these approaches will provide important new information into the molecular basis of azole resistance in A. fumigatus and provide the direct assessment of drug resistance contributions from ABC transporters and the cyp51A gene.

描述（由申请人提供）：由抗唑烟曲霉引起的侵袭性曲霉病具有惊人的12%的存活率，使其成为具有急性意义的临床问题。对烟曲霉抗唑菌株的早期研究表明，对唑的耐药性是相对罕见的，耐药的遗传基础通常是由于编码唑靶蛋白羊毛甾醇α-14去甲基化酶的基因cyp51A的改变。荷兰一个研究小组的广泛研究提供了令人信服的证据，证明在该国，大多数耐唑烟熏假单胞菌分离株含有单一的复合突变，该突变由cyp51A启动子区域（TR34）的重复区域和编码序列的变化组成，改变了蛋白质的氨基酸序列（L98H）。然而，最近来自英国的一个研究小组的研究表明，cyp51A基因的改变不太可能解释烟螨的所有抗唑性。50%以上的唑耐药菌株