Heteroresistance Interdisciplinary Research Unit (Project 2)
异阻性跨学科研究单元(项目2)
基本信息
- 批准号:10583505
- 负责人:
- 金额:$ 55.09万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-03-05 至 2026-02-28
- 项目状态:未结题
- 来源:
- 关键词:Acinetobacter baumanniiAffectAntibiotic ResistanceAntibioticsBacteriaBacterial InfectionsBiologyCellsCessation of lifeCitric Acid CycleClassificationClinicClinicalClinical TrialsComplementConfusionDiffusionEnterobacterEnterobacteriaceaeEuropeExhibitsFormulationFosfomycinFoundationsGene AmplificationGeneticGlucoseGlutamatesGlutathioneGuidelinesHeterogeneityInfectionInterdisciplinary StudyIntermediate resistanceInterventionIntravenousLifeMalignant NeoplasmsMediatingMedicalMetabolicModelingModern MedicineMusMutationOperative Surgical ProceduresOralPathway interactionsPatientsPharmaceutical PreparationsPhenotypePopulationPredispositionPrevalencePrevalence StudyProcessRepressionResearch Project GrantsResistanceRiskRoleSafetyShunt DeviceSignal TransductionTestingTimeTransplantationTreatment FailureTreatment outcomeUrinary tract infectionWorkalpha ketoglutarateantibiotic resistant infectionsbacterial resistancecarbapenem-resistant Enterobacteriaceaechemotherapyclinical diagnosticscombatdesigndrug developmentexperimental studyhuman diseaseimprovedin vivoinsightmembermetabolomicsmortalitynon-geneticnovelnovel strategiesnovel therapeuticspathogenresistance mechanismsugarsurveillance data
项目摘要
ABSTRACT
Antibiotic resistance is one of the most serious medical challenges of our time. This crisis puts patients at risk
of untreatable bacterial infections and threatens major advances of modern medicine that rely on antibiotics
(transplants, chemotherapy, etc). There are at least 2.8 million antibiotic resistant infections each year in the
US, leading to over 35,000 deaths [1]. Without significant action, worldwide annual mortality due to these
infections is predicted to reach 10 million by 2050, surpassing that predicted for cancer [2]. Understanding
resistance mechanisms is critical to designing novel approaches and therapeutics to combat resistant bacteria.
Heteroresistance (HR) is an enigmatic form of antibiotic resistance in which a bacterial isolate harbors a
resistant subpopulation that can rapidly replicate in the presence of an antibiotic, while a susceptible
subpopulation is killed [3, 4]. We have observed HR to the antibiotic, fosfomycin, which is a member of its own
drug class and has primarily been used in the US in an oral form to treat urinary tract infections (UTIs) [5]. The
use of fosfomycin has recently increased as bacteria become resistant to other classes of drugs [6] and due to
its strong safety profile. Due to its increased need and expected expanded approval for IV use,
fosfomycin is expected to become a much more prominent part of the antibiotic arsenal in the US.
Therefore, it is essential that we elucidate the biology of fosfomycin resistance to guide clinical use.
Strikingly, our surveillance data revealed that the rate of fosfomycin HR among carbapenem-resistant
Enterobacteriaceae (CRE; 72%) and Acinetobacter baumannii (CRAB; 89%) was higher than that of any other
antibiotic tested, and that a large proportion was not detected by clinical diagnostics [7]. We recently
demonstrated that HR to diverse antibiotics, including fosfomycin, can cause treatment failure in vivo [4].
Interestingly, and thus far unique among studied examples of HR, we found that fosfomycin HR is caused by
two distinct, co-existing resistant subpopulations, both of which replicate in the presence of drug and are not
persisters, but form resistant small (R-SM) or large (R-LG) colonies. Results from a transposon screen and
metabolomic experiments revealed the underlying basis for the R-SM and R-LG cells to be metabolic
heterogeneity, rather than unstable genetic changes such as gene amplification. We will dissect how metabolic
signaling drives the expansion of the resistant R-SM subpopulation and the roles of glutamate and glutathione
in this process. We will then study the prevalence of distinct fosfomycin resistant subpopulations among
diverse clinical isolates. This work will have a sustained and powerful impact on our understanding of non-
genetic mechanisms of HR and metabolic and phenotypic heterogeneity. This will complement Project 1 which
focuses on unstable genetic mechanisms of HR. The new and fundamental insights gained will lay the
foundation for the discovery of novel therapeutics and interventions targeting subpopulations to
reduce human disease.
摘要
抗生素耐药性是我们这个时代最严重的医学挑战之一。这场危机使病人处于危险之中。
无法治愈的细菌感染,并威胁依赖抗生素的现代医学的重大进步
(移植、化疗等)。在中国,每年至少有280万例耐药感染
导致超过35,000人死亡[1]。如果不采取重大行动,由于这些原因,全球每年的死亡率
预计到2050年,感染人数将达到1000万,超过癌症的预测[2]。理解
耐药机制对于设计对抗耐药细菌的新方法和治疗方法至关重要。
异质性耐药(HR)是一种神秘的抗生素耐药性形式,其中细菌分离物含有
在抗生素存在的情况下可以快速复制的抗药性亚群,而敏感的
亚群被杀[3,4]。我们已经观察到对抗生素磷霉素的HR,它本身就是一个成员
药物类别,在美国主要以口服形式用于治疗尿路感染(UTIs)[5]。这个
随着细菌对其他药物产生抗药性,磷霉素的使用最近有所增加[6],原因是
其强大的安全配置。由于其对静脉注射的需求增加和预期扩大的批准,
磷霉素有望成为美国抗生素军火库中更重要的一部分。
因此,有必要阐明磷霉素耐药的生物学机制,以指导临床用药。
值得注意的是,我们的监测数据显示,在碳青霉烯类耐药的人群中,磷霉素HR的比例
肠杆菌科(CRE;72%)和鲍曼不动杆菌(螃蟹,89%)的感染率较高
抗生素测试,而且临床诊断没有检测到很大一部分[7]。我们最近
证明了包括磷霉素在内的多种抗生素的HR可导致体内治疗失败[4]。
有趣的是,迄今为止,在HR的研究实例中,我们发现磷霉素HR是由
两个不同的、共存的耐药亚群,两者都在药物存在的情况下复制,而不是
持久者,但形成抗性的小(R-SM)或大(R-LG)群体。转座子筛选的结果和
代谢组学实验揭示了R-SM和R-LG细胞代谢的潜在基础
异质性,而不是基因扩增等不稳定的遗传变化。我们将剖析新陈代谢是如何
信号驱动抗性R-SM亚群的扩大及谷氨酸和谷胱甘肽的作用
在这个过程中。然后,我们将研究不同的磷霉素耐药亚群在
不同的临床分离株。这项工作将对我们对非
HR和代谢及表型异质性的遗传机制。这将是对项目1的补充
重点阐述了HR的不稳定遗传机制。所获得的新的和根本的见解将为
发现针对亚群的新疗法和干预措施基金会
减少人类疾病。
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 }}
DAVID S WEISS其他文献
DAVID S WEISS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('DAVID S WEISS', 18)}}的其他基金
Heteroresistance Interdisciplinary Research Unit (Project 2)
异阻性跨学科研究单元(项目2)
- 批准号:
10366038 - 财政年份:2021
- 资助金额:
$ 55.09万 - 项目类别:
CRISPR interference-enabled phenotyping of essential genes in C. difficile to aid in discovery of antibiotic targets
对艰难梭菌中的必需基因进行 CRISPR 干扰表型分析,以帮助发现抗生素靶标
- 批准号:
10369416 - 财政年份:2021
- 资助金额:
$ 55.09万 - 项目类别:
CRISPR interference-enabled phenotyping of essential genes in C. difficile to aid in discovery of antibiotic targets
对艰难梭菌中的必需基因进行 CRISPR 干扰表型分析,以帮助发现抗生素靶标
- 批准号:
10518406 - 财政年份:2021
- 资助金额:
$ 55.09万 - 项目类别:
Heteroresistance Interdisciplinary Research Unit (Project 2)
异阻性跨学科研究单元(项目2)
- 批准号:
10170971 - 财政年份:2021
- 资助金额:
$ 55.09万 - 项目类别:
Heteroresistance Interdisciplinary Research Unit (Admin Core)
异阻性跨学科研究单位(行政核心)
- 批准号:
10170967 - 财政年份:2021
- 资助金额:
$ 55.09万 - 项目类别:
Heteroresistance Interdisciplinary Research Unit (Admin Core)
异阻性跨学科研究单位(行政核心)
- 批准号:
10583498 - 财政年份:2021
- 资助金额:
$ 55.09万 - 项目类别:
Heteroresistance Interdisciplinary Research Unit (Admin Core)
异阻性跨学科研究单位(行政核心)
- 批准号:
10366034 - 财政年份:2021
- 资助金额:
$ 55.09万 - 项目类别:
Exploitation of multiple heteroresistance for effective antibiotic combination therapy
利用多重异质耐药性进行有效的抗生素联合治疗
- 批准号:
10646392 - 财政年份:2020
- 资助金额:
$ 55.09万 - 项目类别:
Exploitation of multiple heteroresistance for effective antibiotic combination therapy
利用多重异质耐药性进行有效的抗生素联合治疗
- 批准号:
10206015 - 财政年份:2020
- 资助金额:
$ 55.09万 - 项目类别:
Exploitation of multiple heteroresistance for effective antibiotic combination therapy
利用多重异质耐药性进行有效的抗生素联合治疗
- 批准号:
10053046 - 财政年份:2020
- 资助金额:
$ 55.09万 - 项目类别:
相似海外基金
RII Track-4:NSF: From the Ground Up to the Air Above Coastal Dunes: How Groundwater and Evaporation Affect the Mechanism of Wind Erosion
RII Track-4:NSF:从地面到沿海沙丘上方的空气:地下水和蒸发如何影响风蚀机制
- 批准号:
2327346 - 财政年份:2024
- 资助金额:
$ 55.09万 - 项目类别:
Standard Grant
BRC-BIO: Establishing Astrangia poculata as a study system to understand how multi-partner symbiotic interactions affect pathogen response in cnidarians
BRC-BIO:建立 Astrangia poculata 作为研究系统,以了解多伙伴共生相互作用如何影响刺胞动物的病原体反应
- 批准号:
2312555 - 财政年份:2024
- 资助金额:
$ 55.09万 - 项目类别:
Standard Grant
How Does Particle Material Properties Insoluble and Partially Soluble Affect Sensory Perception Of Fat based Products
不溶性和部分可溶的颗粒材料特性如何影响脂肪基产品的感官知觉
- 批准号:
BB/Z514391/1 - 财政年份:2024
- 资助金额:
$ 55.09万 - 项目类别:
Training Grant
Graduating in Austerity: Do Welfare Cuts Affect the Career Path of University Students?
紧缩毕业:福利削减会影响大学生的职业道路吗?
- 批准号:
ES/Z502595/1 - 财政年份:2024
- 资助金额:
$ 55.09万 - 项目类别:
Fellowship
Insecure lives and the policy disconnect: How multiple insecurities affect Levelling Up and what joined-up policy can do to help
不安全的生活和政策脱节:多种不安全因素如何影响升级以及联合政策可以提供哪些帮助
- 批准号:
ES/Z000149/1 - 财政年份:2024
- 资助金额:
$ 55.09万 - 项目类别:
Research Grant
感性個人差指標 Affect-X の構築とビスポークAIサービスの基盤確立
建立个人敏感度指数 Affect-X 并为定制人工智能服务奠定基础
- 批准号:
23K24936 - 财政年份:2024
- 资助金额:
$ 55.09万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
How does metal binding affect the function of proteins targeted by a devastating pathogen of cereal crops?
金属结合如何影响谷类作物毁灭性病原体靶向的蛋白质的功能?
- 批准号:
2901648 - 财政年份:2024
- 资助金额:
$ 55.09万 - 项目类别:
Studentship
ERI: Developing a Trust-supporting Design Framework with Affect for Human-AI Collaboration
ERI:开发一个支持信任的设计框架,影响人类与人工智能的协作
- 批准号:
2301846 - 财政年份:2023
- 资助金额:
$ 55.09万 - 项目类别:
Standard Grant
Investigating how double-negative T cells affect anti-leukemic and GvHD-inducing activities of conventional T cells
研究双阴性 T 细胞如何影响传统 T 细胞的抗白血病和 GvHD 诱导活性
- 批准号:
488039 - 财政年份:2023
- 资助金额:
$ 55.09万 - 项目类别:
Operating Grants
How motor impairments due to neurodegenerative diseases affect masticatory movements
神经退行性疾病引起的运动障碍如何影响咀嚼运动
- 批准号:
23K16076 - 财政年份:2023
- 资助金额:
$ 55.09万 - 项目类别:
Grant-in-Aid for Early-Career Scientists














{{item.name}}会员




