Biological consequences of enzymatic inactivation of Pseudomonas pyocyanin
Biological consequences of enzymatic inactivation of Pseudomonas pyocyanin
批准号:
9918822
负责人:
Dianne K Newman
金额:
$52.4万
依托单位国家:
美国
项目类别:
财政年份:
2017
资助国家:
美国
项目状态:
已结题
起止时间:
2017-05-08 至 2022-04-30
关键词:
Active SitesAnaerobic BacteriaAnimal ModelAnimalsAntibiotic susceptibilityAntibioticsBacteriaBiochemicalBiologicalBiological AssayBiological ModelsCellsCiprofloxacinCollaborationsComplexCrystallizationCystic FibrosisCystic Fibrosis sputumCytolysisDevelopmentDistrict of ColumbiaEffectivenessElectron TransportEnvironmentEnzymesExcisionExhibitsEye InfectionsFormaldehydeFoundationsFutureGenerationsGenus MycobacteriumGrowthHomeostasisHumanHydrogen BondingInfectionIronKnowledgeLearningLungLung infectionsMediatingMetabolicMetabolismMicrobeMicrobial BiofilmsModelingMucociliary ClearanceMucolyticsMucous body substanceMycobacterium fortuitumOrganismOxidantsOxidation-ReductionOxygenPatientsPhasePhenazinesPhysiologic tolerancePhysiologyPigmentsPopulationProcessPseudomonasPseudomonas aeruginosaPulmonary FibrosisPyocyanineReactionReactive Oxygen SpeciesResearchResolutionRespiratory physiologySignal TransductionSite-Directed MutagenesisSoilSolventsSpecificityStructureTestingTherapeuticTimeTobramycinVirulence FactorsWaterWorkacute infectionantibiotic toleranceburn woundcell typechronic infectioncystic fibrosis airwaycystic fibrosis patientsdemethylationdiabetic ulcerexperimental studyextracellularfootimprovedinhibitor/antagonistmembermicrobialnovelpathogentherapeutic enzymetreatment strategyventilator-associated pneumonia
中文摘要
项目总结
铜绿假单胞菌是一种在急性感染(烧伤、伤口、呼吸机)中发现的条件致病菌
相关肺炎、眼部感染)和慢性足部感染(糖尿病溃疡)和肺部慢性感染(囊性
纤维化)。这种细菌通常以生物膜的形式存活在这些环境中,形成和高水平
对抗生素的耐受性干扰了有效的患者治疗。铜绿假单胞菌的一个决定性方面是它的
能够制造吩嗪,五颜六色的氧化还原活性颜料,调节各种过程,包括
在生物膜的缺氧内部生存。就像生物膜一样,CF患者肺部聚集的粘液表现为
陡峭的氧气(O2)梯度。随着时间的推移,铜绿假单胞菌通常主导着CF中的微生物种群
肺,因为它的生理允许它在这种环境中茁壮成长。随着氧气浓度的下降,奋乃静类药物增加,
某些吩嗪的浓度,如绿青素(PYO)--动物感染模型中的一种毒力因子--
与肺功能下降有关。虽然PYO是如何产生的,并对不同类型的细胞产生影响(对
制片人,以及对主持人的负面影响)是众所周知的,减少PYO的潜在影响
宿主-病原体相互作用的浓度尚不清楚。最近,我们发现了一种新的PYO去甲基酶
(Poda),由偶发分枝杆菌复合体成员制造,可感染CF患者。宝塔
将PYO转化为1-羟基吩嗪(1OHPHZ),并阻止生物膜的形成和发育。皮奥是
已知可以触发Edna的释放,促进生物膜的形成,以及维持铜绿假单胞菌的厌氧
新陈代谢的过程称为细胞外电子转移(EET)。在PYO丰富的感染中,我们
推测Poda可能通过抑制Edna释放和消除EET来帮助控制铜绿假单胞菌。
正在将PYO转换为10HPHZ。在这里,我们试图对宝塔及其
作为评估其治疗潜力的第一步,抗生物被膜活性的机制。首先,如何
Poda催化PYO去甲基化?第二,移除PYO和10HPHZ的后果是什么
铜绿假单胞菌的形成?第三,Poda的活性是否会增强传统抗生素的有效性
在缓慢生长、氧气限制的生物被膜区控制铜绿假单胞菌?为了回答这些问题,我们
提出两个具体目标。目的1探讨Poda的酶活性及其作用机制
酶的详细信息。目的2探讨Poda抑制铜绿假单胞菌生物被膜的机制
早期和晚期的发育,以及它是否能使铜绿假单胞菌对妥布霉素和
环丙沙星。实现这些目标将为评估所需的基本知识奠定基础
Poda作为治疗酶的潜在用途。
英文摘要
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 phenazines, colorful redox-active pigments that mediate a variety of processes, including
survival within the anoxic interior of biofilms. Like biofilms, mucus collecting in the lungs of CF patients exhibits
steep oxygen (O2) gradients. Over time, P. aeruginosa commonly dominates the microbial population in the CF
lung, as its physiology permits it to thrive in this environment. As O2 declines, phenazines rise, and the
concentration of certain phenazines, such as pyocyanin (PYO)—a virulence factor in animal infection models—
is correlated with declining lung function. While how PYO is made and impacts diverse cell types (positively for
the producer, and negatively for the host) is well understood, the potential impact of reducing PYO
concentration for host-pathogen interactions is unknown. Recently, we discovered a novel PYO demethylase
(PodA) made by members of the Mycobacterium fortuitum complex, which can infect CF patients. PodA
converts PYO to 1-hydroxy-phenazine (1OHPHZ), and blocks biofilm formation and development. PYO is
known to trigger eDNA release and promote biofilm formation, as well as sustain P. aeruginosa's anaerobic
metabolism via a process called extracellular electron transfer (EET). In infections where PYO is abundant, we
hypothesize that PodA might help control P. aeruginosa by inhibiting eDNA release and abrogating EET by
converting PYO to 1OHPHZ. Here, we seek to gain a fundamental scientific understanding of PodA and its
mechanism of anti-biofilm activity as a first step towards evaluating its therapeutic potential. First, how does
PodA catalyze PYO demethylation? Second, what is the consequence of PYO removal and 1OHPHZ
formation for P. aeruginosa? Third, might PodA activity potentiate the effectiveness of conventional antibiotics
in controlling P. aeruginosa in slowly-growing, O2-limited biofilm regions? To answer these questions, we
propose two specific aims. Aim 1 will explore the enzymatic activity and mechanism of action of the PodA
enzyme in detail. Aim 2 will probe the mechanisms underpinning PodA's inhibition of P. aeruginosa biofilm
development at early and late stages, and whether it can sensitize P. aeruginosa to tobramycin and
ciprofloxacin. Attainment of these objectives will lay the foundation of basic knowledge necessary to evaluate
the potential usage of PodA as a therapeutic enzyme.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Testing the hypothesis that microbial energetic hijacking of the CF immune response selects for specific pathogens during lung function decline- Diversity Supplement
-
批准号:10745232
-
项目类别:
-
资助金额:$1.34万
-
财政年份:2023
-
负责人:Dianne K Newman
-
依托单位:
Testing the hypothesis that microbial energetic hijacking of the CF immune response selects for specific pathogens during lung function decline
-
批准号:10175023
-
项目类别:
-
资助金额:$53.11万
-
财政年份:2020
-
负责人:Dianne K Newman
-
依托单位:
Testing the hypothesis that microbial energetic hijacking of the CF immune response selects for specific pathogens during lung function decline
-
批准号:10618780
-
项目类别:
-
资助金额:$45.29万
-
财政年份:2020
-
负责人:Dianne K Newman
-
依托单位:
Testing the hypothesis that microbial energetic hijacking of the CF immune response selects for specific pathogens during lung function decline
-
批准号:10388211
-
项目类别:
-
资助金额:$45.29万
-
财政年份:2020
-
负责人:Dianne K Newman
-
依托单位:
Testing the hypothesis that microbial energetic hijacking of the CF immune response selects for specific pathogens during lung function decline- Diversity Supplement
-
批准号:10818205
-
项目类别:
-
资助金额:$8.74万
-
财政年份:2020
-
负责人:Dianne K Newman
-
依托单位:
Biological mechanisms and consequences of chlorate treatment on Pseudomonas aeruginosa chronic wound infections
-
批准号:9810001
-
项目类别:
-
资助金额:$21.46万
-
财政年份:2019
-
负责人:Dianne K Newman
-
依托单位:
Biological mechanisms and consequences of efficient extracellular electron transfer in Pseudomonas aeruginosa
-
批准号:10660729
-
项目类别:
-
资助金额:$74.75万
-
财政年份:2017
-
负责人:Dianne K Newman
-
依托单位:
Biological consequences of enzymatic inactivation of Pseudomonas pyocyanin
-
批准号:9384435
-
项目类别:
-
资助金额:$54.02万
-
财政年份:2017
-
负责人:Dianne K Newman
-
依托单位:
Geobiological approaches to understanding pulmonary infections in situ
-
批准号:8412666
-
项目类别:
-
资助金额:$41.25万
-
财政年份:2012
-
负责人:Dianne K Newman
-
依托单位:
Geobiological approaches to understanding pulmonary infections in situ
-
批准号:8876780
-
项目类别:
-
资助金额:$41.25万
-
财政年份:2012
-
负责人:Dianne K Newman
-
依托单位:
Geobiological approaches to understanding pulmonary infections in situ
-
批准号:8549295
-
项目类别:
-
资助金额:$40.01万
-
财政年份:2012
-
负责人:Dianne K Newman
-
依托单位:
海外基金