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.
克服烟曲霉中三唑抗性的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,已知的耐药机制确实
不能完全解释大多数临床分离株中观察到的耐药性。我们的长期目标是改善抗真菌药物
治疗,并确保三唑类药物用于治疗由
曲霉属。我们的中心假设是,非cyp 51 A突变介导的机制是必不可少的,
三唑耐药的临床分离的A.烟曲霉和涉及复杂的遗传变化改变1)甾醇
生物合成及其转录激活,2)三唑转运及其转录激活,以及3)迄今为止
未知的机制我们目前的目标是通过识别基因,
和非cyp 51 A突变介导的抗性的分子决定簇。我们的初步数据显示,
虽然cyp 51 A在三唑耐药临床分离株中的突变是常见的,但它们对
阻力很小。我们已经观察到基因突变,这是我们收集的耐药分离株所特有的,
编码甾醇感应蛋白、甾醇生物合成的调节剂和甾醇生物合成酶。我们有
我还观察到临床分离株不仅过表达cyp 51 A,而且过表达麦角甾醇生物合成的大多数基因
途径,表明其组成性激活。我们观察到几个潜在的转运体-
在我们收集的三唑耐药分离株中,
被这些运输者。我们还表明,临床分离的A。烟曲霉通过以下途径摄取三唑类抗真菌剂
促进扩散,我们相信改变三唑进口可能代表了一个重要的机制,
阻力为了实现我们的目标,我们将进行实验,以了解
遗传和分子决定因素通过改变甾醇生物合成或其
转录激活(Aim 1)和三唑转运及其调控(Aim 2)。在目标3中,我们还将利用
无偏见的全基因组比较,加上体外进化实验,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cyp 51 A突变介导的三唑机制
在美国境内活动的抵抗组织基于收集的三唑耐药临床分离株。拟议
研究是重要的,因为它代表了一个全面的分析的分子和遗传基础的非,
cyp 51 A突变介导的A.并将提供新的见解的方式,
可以提高三唑对这种重要的人类病原体的活性。
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)
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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
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{{ 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:
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