Biological mechanisms and consequences of efficient extracellular electron transfer in Pseudomonas aeruginosa
铜绿假单胞菌有效细胞外电子转移的生物学机制和后果
基本信息
- 批准号:10660729
- 负责人:
- 金额:$ 74.75万
- 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:2017-05-08 至 2028-06-30
- 项目状态:未结题
- 来源:
- 关键词:AffectAminoglycosidesAnimalsAntibiotic TherapyAntibioticsBacteriaBioenergeticsBiologicalBurn injuryCellsChargeClinicClinicalColistinConsumptionCystic FibrosisCystic Fibrosis sputumCytolysisDNADefense MechanismsDevelopmentDiffusionElectron TransportElectronsEquilibriumExcisionEye InfectionsFluoroquinolonesFoundationsHomeostasisInfectionKnowledgeLeadLinkLungMeasuresMediatingMetabolicMethodsMicrobial BiofilmsModelingNutrientOxidantsOxidation-ReductionOxygenPatientsPharmaceutical PreparationsPhysiologicalPigmentsPolymersPredispositionPropertyPseudomonasPseudomonas InfectionsPseudomonas aeruginosaPseudomonas aeruginosa infectionPyocyanineReactionRoleSignal TransductionSignaling MoleculeSpecific qualifier valueSystemTechniquesTechnologyTestingVirulence FactorsWorkacute infectionantibiotic tolerancebeta-Lactamsburn woundcell typechronic infectionclinically relevantdesigndiabetic ulcereffective therapyexperimental studyextracellularfitnessfootimprovedin vivoinsightopportunistic pathogenresponseskin woundtooltreatment strategyventilator-associated pneumoniawound
项目摘要
PROJECT SUMMARY
Pseudomonas aeruginosa is an opportunistic pathogen found in acute infections (burns, wounds, ventilator
associated pneumonia, eye infections) and chronic infections of the foot (diabetic ulcers) and lung (cystic
fibrosis). This bacterium commonly survives in these contexts as a biofilm, the formation and high-level
antibiotic tolerance of which interferes with effective patient treatment. A defining aspect of P. aeruginosa is its
ability to make pyocyanin, a colorful redox-active pigment that contributes to biofilm development and its
fitness in the context of infection. Pyocyanin has been detected at appreciable concentrations in skin wounds
and in cystic fibrosis sputum, and pyocyanin has been shown to be a virulence factor in animal infection
models. Pyocyanin exerts a range of effects over the cells that produce it, ranging from toxic in the presence of
oxygen to beneficial in its absence; under oxygen-limited conditions, pyocyanin serves as an electron acceptor
that promotes redox-balancing and long-term survival. These toxic and beneficial roles are important at
different times in biofilm development, with early pyocyanin -promoted lysis generating extracellular DNA
(eDNA), a key component of the biofilm matrix together with exopolysaccharides. Recently, we determined that
eDNA underpins pyocyanin’s ability to promote extracellular electron transfer (EET) within biofilms, facilitating
metabolic activity in the oxygen-limited interior. We found that eDNA enables both the retention of pyocyanin
and charge transfer to pyocyanin. Critical to making these discoveries was our development of new
bioelectrochemical technologies and approaches and the application of advanced spectroscopic techniques to
directly probe EET in biofilms. We now seek to extend our interdisciplinary work to gain a mechanistic
understanding of how biofilm EET efficiency is tuned by the composition of the matrix and the consequences
this may have for antibiotic tolerance. Does the ratio of certain exopolysaccharides (Pel, Psl) to eDNA
modulate pyocyanin diffusivity in the matrix, controlling EET efficiency? Does EET efficiency correlate with the
rate of redox balancing in the biofilm interior? How do pyocyanin-mediated cellular effects, including EET,
contribute to antibiotic tolerance in biofilms, and do these mechanisms differ according to the amount of
oxygen in the microenvironment? Does the relative sensitivity of diverse pyocyanin-producing P. aeruginosa
isolates to antibiotics correlate with their matrix composition and EET efficiency? Aim1 will explore how the
matrix composition, particularly the ratio of Pel and Psl exopolysaccharides to eDNA, determines EET
efficiency. Aim 2 will test the hypothesis that pyocyanin is a versatile intrinsic tolerance factor, where PYO-EET
helps P. aeruginosa biofilms tolerate mechanistically distinct and clinically important antibiotic classes via
bioenergetic effects and/or by inducing defense mechanisms; we predict the dominant mechanism by which
PYO impacts tolerance will differ as a function of oxygen concentration. Attainment of these objectives will lay
the foundation of basic knowledge necessary to design better strategies to control P. aeruginosa biofilms.
项目摘要
铜绿假单胞菌是一种机会致病菌,在急性感染(烧伤,创伤,呼吸机
相关性肺炎、眼部感染)以及足部(糖尿病溃疡)和肺部(囊性
纤维化)。这种细菌通常以生物膜的形式在这些环境中生存,其形成和高水平的
其抗生素耐受性干扰有效的患者治疗。铜绿假单胞菌的一个定义方面是其
绿脓菌素是一种彩色的氧化还原活性色素,有助于生物膜的发育,
在感染的背景下,绿脓菌素已被检测到在皮肤伤口的可观浓度
和囊性纤维化痰中,绿脓菌素已被证明是动物感染中的毒力因子
模型绿脓菌素对产生它的细胞有一系列的影响,从在存在的情况下有毒,
氧在它的缺席是有益的;在氧限制的条件下,绿脓菌素作为电子受体
促进氧化还原平衡和长期生存。这些有毒和有益的作用是重要的,
在生物膜发育的不同时期,早期绿脓菌素促进裂解产生胞外DNA
DNA是生物膜基质的关键组分,与胞外多糖一起。最近,我们确定,
eDNA支持绿脓菌素促进生物膜内细胞外电子转移(EET)的能力,
在氧气有限的内部进行代谢活动。我们发现eDNA既能保留绿脓菌素,
并将电荷转移到绿脓菌素。做出这些发现的关键是我们开发了新的
生物电化学技术和方法以及先进的光谱技术在
直接探测生物膜中的EET。我们现在寻求扩展我们的跨学科工作,以获得一个机械的
了解生物膜EET效率如何通过基质的组成和结果来调节
这可能导致了抗生素耐药性。某些胞外多糖(Pel,Psl)与eDNA的比例
调节绿脓菌素在基质中的扩散,控制EET效率?EET效率是否与
在生物膜内部的氧化还原平衡率?绿脓菌素介导的细胞效应,包括EET,
有助于生物膜中的抗生素耐受性,并且这些机制是否根据抗生素的量而不同?
微环境中的氧气不同绿脓杆菌的相对敏感性是否
分离株对抗生素的敏感性与其基质组成和EET效率相关吗?AIM 1将探索如何
基质组成,特别是Pel和Psl胞外多糖与eDNA的比例,决定了EET
效率目的2将检验绿脓菌素是一种多功能的内在耐受因子的假设,其中PYO-EET
帮助铜绿假单胞菌生物膜耐受机械上不同的和临床上重要的抗生素类,
生物能量效应和/或诱导防御机制;我们预测的主导机制,
PYO影响耐受性将作为氧浓度的函数而不同。这些目标的实现,
为设计更好的控制铜绿假单胞菌生物膜的策略奠定基础。
项目成果
期刊论文数量(34)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
The Colorful World of Extracellular Electron Shuttles.
- DOI:10.1146/annurev-micro-090816-093913
- 发表时间:2017-09-08
- 期刊:
- 影响因子:10.5
- 作者:Glasser NR;Saunders SH;Newman DK
- 通讯作者:Newman DK
Soil bacteria protect fungi from phenazines by acting as toxin sponges.
- DOI:10.1016/j.cub.2021.11.002
- 发表时间:2022-01-24
- 期刊:
- 影响因子:0
- 作者:Dahlstrom KM;Newman DK
- 通讯作者:Newman DK
Redox-active antibiotics enhance phosphorus bioavailability.
- DOI:10.1126/science.abd1515
- 发表时间:2021-03-05
- 期刊:
- 影响因子:0
- 作者:McRose DL;Newman DK
- 通讯作者:Newman DK
Identification of Fitness Determinants during Energy-Limited Growth Arrest in Pseudomonas aeruginosa.
- DOI:10.1128/mbio.01170-17
- 发表时间:2017-11-28
- 期刊:
- 影响因子:6.4
- 作者:Basta DW;Bergkessel M;Newman DK
- 通讯作者:Newman DK
Nitrate Reduction Stimulates and Is Stimulated by Phenazine-1-Carboxylic Acid Oxidation by Citrobacter portucalensis MBL.
硝酸盐还原刺激并通过柠檬酸杆菌portucalensis mbl刺激苯嗪-1-羧酸氧化。
- DOI:10.1128/mbio.02265-21
- 发表时间:2021-08-31
- 期刊:
- 影响因子:6.4
- 作者:Tsypin LM;Newman DK
- 通讯作者:Newman DK
{{
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 }}
Dianne K Newman其他文献
Rethinking 'secondary' metabolism: physiological roles for phenazine antibiotics
重新思考“次级”代谢:吩嗪抗生素的生理作用
- DOI:
10.1038/nchembio764 - 发表时间:
2006-01-18 - 期刊:
- 影响因子:13.700
- 作者:
Alexa Price-Whelan;Lars E P Dietrich;Dianne K Newman - 通讯作者:
Dianne K Newman
Biofilms as more than the sum of their parts: lessons from developmental biology
生物膜不只是其各部分的总和:来自发育生物学的教训
- DOI:
10.1016/j.mib.2024.102537 - 发表时间:
2024-12-01 - 期刊:
- 影响因子:7.500
- 作者:
Georgia R Squyres;Dianne K Newman - 通讯作者:
Dianne K Newman
Dianne K Newman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('Dianne K Newman', 18)}}的其他基金
Testing the hypothesis that microbial energetic hijacking of the CF immune response selects for specific pathogens during lung function decline- Diversity Supplement
测试以下假设:微生物对 CF 免疫反应的能量劫持会在肺功能下降期间选择特定病原体 - Diversity Supplement
- 批准号:
10745232 - 财政年份:2023
- 资助金额:
$ 74.75万 - 项目类别:
Testing the hypothesis that microbial energetic hijacking of the CF immune response selects for specific pathogens during lung function decline
检验以下假设:CF 免疫反应的微生物能量劫持会在肺功能下降期间选择特定病原体
- 批准号:
10175023 - 财政年份:2020
- 资助金额:
$ 74.75万 - 项目类别:
Testing the hypothesis that microbial energetic hijacking of the CF immune response selects for specific pathogens during lung function decline
检验以下假设:CF 免疫反应的微生物能量劫持会在肺功能下降期间选择特定病原体
- 批准号:
10618780 - 财政年份:2020
- 资助金额:
$ 74.75万 - 项目类别:
Testing the hypothesis that microbial energetic hijacking of the CF immune response selects for specific pathogens during lung function decline
检验以下假设:CF 免疫反应的微生物能量劫持会在肺功能下降期间选择特定病原体
- 批准号:
10388211 - 财政年份:2020
- 资助金额:
$ 74.75万 - 项目类别:
Testing the hypothesis that microbial energetic hijacking of the CF immune response selects for specific pathogens during lung function decline- Diversity Supplement
测试以下假设:微生物对 CF 免疫反应的能量劫持会在肺功能下降期间选择特定病原体 - Diversity Supplement
- 批准号:
10818205 - 财政年份:2020
- 资助金额:
$ 74.75万 - 项目类别:
Biological mechanisms and consequences of chlorate treatment on Pseudomonas aeruginosa chronic wound infections
氯酸盐治疗铜绿假单胞菌慢性伤口感染的生物学机制和后果
- 批准号:
9810001 - 财政年份:2019
- 资助金额:
$ 74.75万 - 项目类别:
Biological consequences of enzymatic inactivation of Pseudomonas pyocyanin
绿脓杆菌酶灭活的生物学后果
- 批准号:
9384435 - 财政年份:2017
- 资助金额:
$ 74.75万 - 项目类别:
Biological consequences of enzymatic inactivation of Pseudomonas pyocyanin
绿脓杆菌酶灭活的生物学后果
- 批准号:
9918822 - 财政年份:2017
- 资助金额:
$ 74.75万 - 项目类别:
Geobiological approaches to understanding pulmonary infections in situ
了解原位肺部感染的地球生物学方法
- 批准号:
8412666 - 财政年份:2012
- 资助金额:
$ 74.75万 - 项目类别:
Geobiological approaches to understanding pulmonary infections in situ
了解原位肺部感染的地球生物学方法
- 批准号:
8876780 - 财政年份:2012
- 资助金额:
$ 74.75万 - 项目类别:
相似海外基金
Aminoglycosides with reduced ototoxicity via miRNA targeting
通过 miRNA 靶向降低耳毒性的氨基糖苷类药物
- 批准号:
9891947 - 财政年份:2019
- 资助金额:
$ 74.75万 - 项目类别:
Aminoglycosides with reduced ototoxicity via miRNA targeting
通过 miRNA 靶向降低耳毒性的氨基糖苷类药物
- 批准号:
9982540 - 财政年份:2019
- 资助金额:
$ 74.75万 - 项目类别:
Antibacterial properties of amphiphilic aminoglycosides
两亲性氨基糖苷类药物的抗菌特性
- 批准号:
524825-2018 - 财政年份:2018
- 资助金额:
$ 74.75万 - 项目类别:
University Undergraduate Student Research Awards
Nanobiocapteurs de résonance des plasmons de surface pour les aminoglycosides
氨基糖苷类表面等离激元共振的纳米生物捕获剂
- 批准号:
495915-2016 - 财政年份:2016
- 资助金额:
$ 74.75万 - 项目类别:
Alexander Graham Bell Canada Graduate Scholarships - Master's
Designing new aminoglycosides to alleviate inner ear toxicity
设计新的氨基糖苷类药物以减轻内耳毒性
- 批准号:
8943277 - 财政年份:2015
- 资助金额:
$ 74.75万 - 项目类别: