Non-cyp51A-mutation Mediated Triazole Resistance in Aspergillus fumigatus
非 cyp51A 突变介导的烟曲霉三唑耐药性
基本信息
- 批准号:10582526
- 负责人:
- 金额:$ 65.73万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-03-01 至 2025-02-28
- 项目状态:未结题
- 来源:
- 关键词:3-hydroxy-3-methylglutaryl-coenzyme AAddressAffectAllelesAnabolismAntifungal AgentsAntifungal TherapyAspergillosisAspergillusAspergillus fumigatusAutomobile DrivingAzole resistanceAzolesCRISPR/Cas technologyClinicalCollectionComplexCoupledDNA Sequence AlterationDataDiagnosisDiffusionDiseaseDrug TransportEnsureErgosterolEvolutionExhibitsFungal Drug ResistanceGene Expression ProfileGene Expression ProfilingGenesGeneticGenomeGenomicsGoalsImmunocompromised HostIn VitroIndividualInfectionKnowledgeLaboratoriesMediatingMethodsMoldsMolecularMolecular AnalysisMorbidity - disease rateMutationOutcomeOxidoreductasePathway interactionsPlayPredispositionProteinsRegulationResearchResistanceResistance developmentResistance profileRiskRoleSequence AnalysisSterol Biosynthesis PathwaySterolsSystemTechniquesTestingTherapeuticTranscriptional ActivationTranslatingTreatment FailureVoriconazoleWorkclinical predictorsclinically relevantdifferential expressioneffective therapyenzyme biosynthesisexperimental studygenetic analysisgenetic manipulationgenome analysishuman pathogenimprovedinhibitorinnovationinsightmortalitymutantnovelnovel strategiesoverexpressionpatient populationpreventpublic health relevanceresistance mechanismresistance mutationresistant Aspergillusstemtreatment choicewhole genome
项目摘要
A critical barrier to overcoming triazole resistance in Aspergillus fumigatus is the significant lack of
understanding of its genetic and molecular basis. We have shown that the known mechanisms of resistance do
not fully explain resistance observed among most clinical isolates. Our long-term goal is to improve antifungal
therapy and ensure the sustained clinical utility of the triazole class for treatment of infections caused by
Aspergillus species. Our central hypothesis is that non-cyp51A-mutation mediated mechanisms are essential
to triazole resistance in clinical isolates of A. fumigatus and involve complex genetic changes altering 1) sterol
biosynthesis and its transcriptional activation, 2) triazole transport and its transcriptional activation, and 3) as yet
unknown mechanisms. Our current objective is to address critical knowledge gaps by identifying the genetic
and molecular determinants of non-cyp51A-mutation mediated resistance. Our preliminary data suggest that
while mutations in cyp51A among triazole resistant clinical isolates are common, their overall contribution to
resistance is minimal. We have observed mutations, unique to resistant isolates in our collection, in genes
encoding sterol sensing proteins, regulators of sterol biosynthesis, and sterol biosynthesis enzymes. We have
also observed clinical isolates that overexpress not only cyp51A, but most genes of the ergosterol biosynthesis
pathway, suggesting its constitutive activation. We have observed several potential transporters that are up-
regulated among triazole resistant isolates in our collection, suggesting a role for triazole efflux and resistance
by these transporters. We have also shown that clinical isolates of A. fumigatus take up triazole antifungals via
facilitated diffusion and we believe that altered triazole import may represent an important mechanism of
resistance. To accomplish our objective we will undertake experiments that will lead to an understanding of what
genetic and molecular determinants influence triazole susceptibility through altered sterol biosynthesis or its
transcriptional activation (Aim 1) and triazole transport and its regulation (Aim 2). In Aim 3, we will also utilize an
unbiased whole genome comparisons, coupled with in vitro evolution experiments, to identify completely novel
mechanisms of resistance in clinical isolates. Our approach is innovative as we will use the latest genetic and
genomic techniques to study and discover novel non-cyp51A-mutation mediated mechanisms of triazole
resistance that are operative in a U.S.-based collection of triazole resistant clinical isolates. The proposed
research is significant as it represents a comprehensive analysis of the molecular and genetic basis of non-
cyp51A-mutation mediated triazole resistance in A. fumigatus and will provide novel insights into ways in which
triazole activity can be improved against this important human pathogen.
克服烟曲霉对三氮唑耐药性的一个关键障碍是显著缺乏
了解其遗传和分子基础。我们已经证明,已知的抗药性机制确实
不能完全解释在大多数临床分离株中观察到的耐药性。我们的长期目标是提高抗真菌能力
治疗并确保三氮唑类药物治疗由以下原因引起的感染
曲霉菌种。我们的中心假设是非cyp51a突变机制是必不可少的。
临床分离烟曲霉菌对三氮唑的耐药性和涉及改变1)甾醇的复杂基因变化
生物合成及其转录激活,2)三氮唑转运及其转录激活,3)尚未
未知的机制。我们目前的目标是通过识别基因,解决关键的知识差距
以及非cyp51a突变介导的抗性的分子决定因素。我们的初步数据表明
虽然cyp51a基因突变在对三氮唑耐药的临床分离株中很常见,但它们对
阻力是最小的。我们观察到了我们收集的耐药菌株所特有的基因突变。
编码类固醇感应蛋白、类固醇生物合成调节剂和类固醇生物合成酶。我们有
还观察到临床分离株不仅过度表达cyp51a,而且过度表达麦角固醇生物合成的大部分基因。
途径,提示其结构性激活。我们观察到了几个潜在的传输器正在运行-
在我们收集的三氮唑耐药分离株中进行调节,提示三氮唑外排和耐药性的作用
被这些传送者。我们还发现,烟曲霉菌的临床分离株通过
促进了扩散,我们认为改变的三氮唑进口可能代表了
抵抗。为了实现我们的目标,我们将进行实验,以了解
基因和分子决定因素通过改变甾醇的生物合成或改变其对三氮唑的敏感性而影响其敏感性
转录激活(目标1)和三氮唑转运及其调控(目标2)。在目标3中,我们还将利用
无偏见的全基因组比较,结合体外进化实验,以确定完全新的
临床分离株的耐药机制。我们的方法是创新的,因为我们将使用最新的基因和
基因组技术研究和发现新的非cyp51a突变介导的三氮唑作用机制
在美国的三氮唑耐药临床分离株集合中起作用的耐药性。建议数
这项研究具有重要意义,因为它代表了对非传染性疾病的分子和遗传学基础的全面分析
Cyp51a突变介导了烟曲霉菌对三氮唑的耐药性,并将为研究
三氮唑对这种重要的人类病原体的活性可以提高。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Jarrod R. Fortwendel其他文献
MOB-mediated regulation of septation initiation network (SIN) signaling is required for echinocandin-induced hyperseptation in emAspergillus fumigatus/em
棘白菌素诱导烟曲霉超分隔需要 MOB 介导的分隔起始网络(SIN)信号调节
- DOI:
10.1128/msphere.00695-23 - 发表时间:
2024-02-20 - 期刊:
- 影响因子:3.100
- 作者:
Harrison I. Thorn;Xabier Guruceaga;Adela Martin-Vicente;Ashley V. Nywening;Jinhong Xie;Wenbo Ge;Jarrod R. Fortwendel;Rebecca S. Shapiro - 通讯作者:
Rebecca S. Shapiro
emhapE/em and emhmg1/em Mutations Are Drivers of emcyp51A/em-Independent Pan-Triazole Resistance in an Aspergillus fumigatus Clinical Isolate
emhapE/em 和 emhmg1/em 突变是烟曲霉临床分离株中不依赖于 emcyp51A/em 的泛三唑抗性的驱动因素
- DOI:
10.1128/spectrum.05188-22 - 发表时间:
2023-05-18 - 期刊:
- 影响因子:3.800
- 作者:
Ana C. O. Souza;Wenbo Ge;Nathan P. Wiederhold;Jeffrey M. Rybak;Jarrod R. Fortwendel;P. David Rogers - 通讯作者:
P. David Rogers
Jarrod R. Fortwendel的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Jarrod R. Fortwendel', 18)}}的其他基金
Genetic Determinants of Aspergillus host-pathogen interactions
曲霉菌宿主-病原体相互作用的遗传决定因素
- 批准号:
10724816 - 财政年份:2023
- 资助金额:
$ 65.73万 - 项目类别:
Unlocking the cidal activity of echinocandins against Aspergillus fumigatus
解锁棘白菌素对烟曲霉的杀灭活性
- 批准号:
10378147 - 财政年份:2021
- 资助金额:
$ 65.73万 - 项目类别:
Unlocking the cidal activity of echinocandins against Aspergillus fumigatus
解锁棘白菌素对烟曲霉的杀灭活性
- 批准号:
10179720 - 财政年份:2021
- 资助金额:
$ 65.73万 - 项目类别:
Unlocking the cidal activity of echinocandins against Aspergillus fumigatus
解锁棘白菌素对烟曲霉的杀灭活性
- 批准号:
10590730 - 财政年份:2021
- 资助金额:
$ 65.73万 - 项目类别:
Non-cyp51A-mutation Mediated Triazole Resistance in Aspergillus fumigatus
非 cyp51A 突变介导的烟曲霉三唑耐药性
- 批准号:
9913275 - 财政年份:2020
- 资助金额:
$ 65.73万 - 项目类别:
Non-cyp51A-mutation Mediated Triazole Resistance in Aspergillus fumigatus
非 cyp51A 突变介导的烟曲霉三唑耐药性
- 批准号:
10358515 - 财政年份:2020
- 资助金额:
$ 65.73万 - 项目类别:
Fungal Ras-mediated invasive growth mechanisms
真菌 Ras 介导的侵袭性生长机制
- 批准号:
9282239 - 财政年份:2014
- 资助金额:
$ 65.73万 - 项目类别:
Fungal Ras-mediated invasive growth mechanisms
真菌 Ras 介导的侵袭性生长机制
- 批准号:
8806512 - 财政年份:2014
- 资助金额:
$ 65.73万 - 项目类别:
Fungal Ras-mediated invasive growth mechanisms
真菌 Ras 介导的侵袭性生长机制
- 批准号:
9205482 - 财政年份:2014
- 资助金额:
$ 65.73万 - 项目类别:
Fungal Ras-mediated invasive growth mechanisms
真菌 Ras 介导的侵袭性生长机制
- 批准号:
8696215 - 财政年份:2014
- 资助金额:
$ 65.73万 - 项目类别:
相似海外基金
Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
- 批准号:
MR/S03398X/2 - 财政年份:2024
- 资助金额:
$ 65.73万 - 项目类别:
Fellowship
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
- 批准号:
EP/Y001486/1 - 财政年份:2024
- 资助金额:
$ 65.73万 - 项目类别:
Research Grant
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
- 批准号:
2338423 - 财政年份:2024
- 资助金额:
$ 65.73万 - 项目类别:
Continuing Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
- 批准号:
MR/X03657X/1 - 财政年份:2024
- 资助金额:
$ 65.73万 - 项目类别:
Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
- 批准号:
2348066 - 财政年份:2024
- 资助金额:
$ 65.73万 - 项目类别:
Standard Grant
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
- 批准号:
2341402 - 财政年份:2024
- 资助金额:
$ 65.73万 - 项目类别:
Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
- 批准号:
AH/Z505481/1 - 财政年份:2024
- 资助金额:
$ 65.73万 - 项目类别:
Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10107647 - 财政年份:2024
- 资助金额:
$ 65.73万 - 项目类别:
EU-Funded
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10106221 - 财政年份:2024
- 资助金额:
$ 65.73万 - 项目类别:
EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
- 批准号:
AH/Z505341/1 - 财政年份:2024
- 资助金额:
$ 65.73万 - 项目类别:
Research Grant