Aspergillus fumigatus Volatile Secondary Metabolite Dynamics for the Identification of Azole-resistant Aspergillosis
烟曲霉挥发性次生代谢动态用于鉴定唑类抗性曲霉病
基本信息
- 批准号:9299327
- 负责人:
- 金额:$ 25.63万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-03-01 至 2019-02-28
- 项目状态:已结题
- 来源:
- 关键词:AgricultureAllergic Bronchopulmonary AspergillosisAnabolismAntifungal AgentsAntifungal TherapyAsiaAspergillosisAspergillusAspergillus fumigatusAttenuatedAzole resistanceAzolesBiological AssayBreath TestsBreathingCell DeathCessation of lifeChronicClinicalConsensusCytochrome P450DataDetectionDevelopmentDiagnostic ProcedureDiagnostic testsEarly identificationEnvironmentErgosterolEuropeExplosionFailureFungal Drug ResistanceGas ChromatographyGeographic DistributionGrowthGuidelinesImmune systemImmunocompromised HostIn VitroIncidenceIndustrial fungicideInfectionItraconazoleLanosterolLungMedicalMetabolicMethodsModelingMorbidity - disease rateMusMutationNephrotoxicPatientsPharmaceutical PreparationsPhenotypePolyenesReportingResistanceRiskRisk FactorsSesquiterpenesSoilSpectrometryStructureTestingTherapeuticTimeToxic effectTriazolesVoriconazoleWaterWorkattenuationbaseclinical riskexperimental studyfungusin vivomortalitynephrotoxicitynovelpressureresistance mechanismresponsesoil samplingtandem mass spectrometry
项目摘要
Project Summary/Abstract: Invasive aspergillosis (IA) is a leading cause of morbidity and death in
immunocompromised patients, with over 200,000 cases worldwide per year. While advances in diagnostic testing
for IA and the development of potent, less toxic triazole antifungal drugs have reduced IA-associated mortality from
68% to 25%, an alarming rise in the incidence and geographic distribution of azole-resistant Aspergillus fumigatus
(ARAF) over the past decade is steadily offsetting these gains and compromising the use of triazole antifungal drugs
as first-line therapy for IA. The major culprit in the rapid explosion of ARAF in the environment and in patient
lungs appears to be the increasing global use of azole fungicides similar in structure to medical triazoles in
agriculture worldwide, especially in Europe and Asia – these fungicides persist in the soil and water for months,
applying widespread, systematic selection pressure favoring the emergence of ARAF, which in turn spreads quickly
through vegetative growth and abundant dissemination of airborne conidia. ARAF is now responsible for up to 30%
of IA cases in Europe with associated mortality of 70-100%, with steadily rising incidence elsewhere in the world.
Managing patients with ARAF IA is incredibly challenging due to the lack of clinical risk factors, lack of diagnostic
methods that can differentiate ARAF IA from azole-susceptible IA in a timely manner, and the need to employ
antifungals with substantially lower efficacy and greater toxicity than the azole drugs. We have developed methods
of identifying patients with IA via detection of Aspergillus volatile sesquiterpene secondary metabolites in breath,
and of examining in vivo responses to antifungal treatment via serial assessment of these fungal breath metabolites
over the course of antifungal therapy. In contrast to the attenuation of secondary metabolite release in azole-
susceptible A. fumigatus with azole antifungal treatment, these metabolites instead increase in ARAF with azole
exposure. We will test the hypothesis that the sesquiterpene secondary metabolite response to triazole antifungal
therapy is distinct in azole-susceptible and azole-resistant A. fumigatus by (1) comparing the in vitro response of
ARAF (including the most common cyp51A mutations TR34/L98H, TR46/Y121F/T289A, M220, and G54, and ARAF
with phenotypic multi-azole resistance despite wild-type cyp51A) and azole-susceptible A. fumigatus strains to
azole antifungal therapy and (2) comparing the in vivo response of ARAF and azole-susceptible A. fumigatus to
azole antifungal therapy in breath using a neutropenic murine IA model. Ultimately, we expect to delineate
marked differences in the dynamics of volatile sesquiterpene secondary metabolite release in ARAF vs. azole-
susceptible A. fumigatus, both in vitro and in vivo. Successful completion of these aims would set the
groundwork for a novel, rapid breath assay that can distinguish patients with ARAF IA from azole-susceptible
IA, providing an in vivo indicator of imminent therapeutic failure, guiding selection of appropriate antifungal
therapy, and reducing the extremely high morbidity and mortality associated with ARAF IA.
项目摘要/摘要:侵袭性曲霉菌病(IA)是一个主要的发病率和死亡原因,
免疫功能低下的患者,全球每年超过20万例。虽然诊断测试的进步
以及强效、毒性较小的三唑类抗真菌药物的开发降低了IA相关的死亡率,
68%至25%,耐唑烟曲霉的发病率和地理分布出现了惊人的上升
在过去的十年中,ARAF正在稳步抵消这些收益,并影响三唑类抗真菌药物的使用
作为IA的一线治疗ARAF在环境和患者中迅速爆炸的主要原因
肺似乎是越来越多的全球使用唑类杀真菌剂类似的结构,以医疗三唑,
全球农业,特别是在欧洲和亚洲-这些杀真菌剂在土壤和水中持续数月,
施加广泛的、系统的选择压力,有利于ARAF的出现,而ARAF又迅速传播
通过营养生长和大量的气载分生孢子传播。ARAF现在负责高达30%的
在欧洲,IA病例的相关死亡率为70- 100%,世界其他地区的发病率稳步上升。
由于缺乏临床风险因素,缺乏诊断标准,
能够及时区分ARAF IA和唑类敏感IA的方法,以及采用
与唑类药物相比,抗真菌药物的疗效要低得多,毒性更大。
通过检测呼吸中曲霉挥发性倍半萜次级代谢产物来鉴定IA患者,
以及通过对这些真菌呼吸代谢物的系列评估来检查抗真菌治疗的体内反应
在抗真菌治疗的过程中与唑类药物中次级代谢产物释放的衰减相反,
易感的A.烟曲霉用唑类抗真菌药治疗后,这些代谢产物反而增加了ARAF与唑类
exposure.我们将检验倍半萜次级代谢产物对三唑类抗真菌药物的反应的假设
对唑类药物敏感和耐药的A.通过(1)比较以下物质的体外反应:
ARAF(包括最常见的cyp 51 A突变TR 34/L98 H、TR 46/Y121 F/T289 A、M220和G54,以及ARAF)
尽管野生型cyp 51 A具有表型多唑抗性)和唑敏感A.烟曲霉菌株,
比较ARAF和唑类敏感A.烟熏,
唑类抗真菌治疗的呼吸使用血小板减少的小鼠IA模型。最终,我们希望能描绘出
ARAF与唑类中挥发性倍半萜次级代谢产物释放动力学的显著差异-
易感A.烟曲霉,在体外和体内。成功实现这些目标将为
一种新的快速呼吸试验的基础,可以区分ARAF IA患者和唑敏感患者。
IA,提供即将发生治疗失败的体内指标,指导选择适当的抗真菌药物
治疗,并降低与ARAF IA相关的极高发病率和死亡率。
项目成果
期刊论文数量(0)
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Sophia Koo其他文献
Sophia Koo的其他文献
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{{ truncateString('Sophia Koo', 18)}}的其他基金
A Novel Device for Rapid and Noninvasive Volatile Metabolite-based Screening and Diagnosis of Multiple Disease States
一种基于挥发性代谢物的快速、无创筛查和诊断多种疾病状态的新型装置
- 批准号:
10663172 - 财政年份:2022
- 资助金额:
$ 25.63万 - 项目类别:
A Novel Device for Rapid and Noninvasive Volatile Metabolite-based Screening and Diagnosis of Multiple Disease States
一种基于挥发性代谢物的快速、无创筛查和诊断多种疾病状态的新型装置
- 批准号:
10426603 - 财政年份:2022
- 资助金额:
$ 25.63万 - 项目类别:
Breath Volatile Metabolites for the Diagnosis of Coccidioidomycosis
呼吸挥发性代谢物用于球孢子菌病的诊断
- 批准号:
10312113 - 财政年份:2020
- 资助金额:
$ 25.63万 - 项目类别:
Rapid, Breath Volatile Metabolite-Based Diagnostic for In Vivo Identification and Antibiotic Resistance Profiling of Bacterial Pathogens in Ventilator-Associated Pneumonia
基于呼吸挥发性代谢物的快速诊断,用于呼吸机相关肺炎细菌病原体的体内鉴定和抗生素耐药性分析
- 批准号:
10630048 - 财政年份:2018
- 资助金额:
$ 25.63万 - 项目类别:
Rapid, Breath Volatile Metabolite-Based Diagnostic for In Vivo Identification and Antibiotic Resistance Profiling of Bacterial Pathogens in Ventilator-Associated Pneumonia
基于呼吸挥发性代谢物的快速诊断,用于呼吸机相关肺炎细菌病原体的体内鉴定和抗生素耐药性分析
- 批准号:
9922858 - 财政年份:2018
- 资助金额:
$ 25.63万 - 项目类别:
Volatile Metabolite-Based Detection of Clostridium difficile Infection
基于挥发性代谢物的艰难梭菌感染检测
- 批准号:
9088345 - 财政年份:2015
- 资助金额:
$ 25.63万 - 项目类别:
Breath Volatile Metabolites for the Diagnosis of Emerging Invasive Mold Infection
呼吸挥发性代谢物用于诊断新发侵袭性霉菌感染
- 批准号:
8875578 - 财政年份:2012
- 资助金额:
$ 25.63万 - 项目类别:
Breath Volatile Metabolites for the Diagnosis of Emerging Invasive Mold Infection
呼吸挥发性代谢物用于诊断新发侵袭性霉菌感染
- 批准号:
8528464 - 财政年份:2012
- 资助金额:
$ 25.63万 - 项目类别:
Breath Volatile Metabolites for the Diagnosis of Emerging Invasive Mold Infection
呼吸挥发性代谢物用于诊断新发侵袭性霉菌感染
- 批准号:
8699494 - 财政年份:2012
- 资助金额:
$ 25.63万 - 项目类别:
Breath Volatile Metabolites for the Diagnosis of Emerging Invasive Mold Infection
呼吸挥发性代谢物用于诊断新发侵袭性霉菌感染
- 批准号:
8443160 - 财政年份:2012
- 资助金额:
$ 25.63万 - 项目类别:
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