A Population-Level Analysis of Novel Antimicrobial Production Among Wild Marine V
野生海洋 V 中新型抗菌剂生产的群体水平分析
基本信息
- 批准号:8433969
- 负责人:
- 金额:$ 31.61万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-01-01 至 2016-12-31
- 项目状态:已结题
- 来源:
- 关键词:AffectAntibioticsAntimicrobial ResistanceBacteriaBacterial InfectionsCessation of lifeCholeraDataDiseaseDisease OutbreaksEarthquakesEctopic ExpressionEnvironmentEpidemicExposure toFloridaFutureGene DeletionGenesGeneticGenetic TechniquesGoalsGrowthHabitatsHaitiHealthHealthcare SystemsHumanHurricaneIndividualInfectionInvestigationLatin AmericaLeadLocalesMarinesMedicalMethodologyMethodsMinorityMolecularMutagenesisOutcomeOystersPathogenicityPatternPhylogenetic AnalysisPopulationPredispositionProcessProductionRecurrenceReportingResearchResearch DesignResearch InfrastructureResistanceRiskSamplingSeafoodSerotypingStructureStudentsSystemTestingTimeTrainingUnited StatesVibrioVibrio choleraeVibrio cholerae non-O1Vibrio parahaemolyticusVibrio vulnificusVibrionaceaeVirulentWorkantibiotic designantimicrobialantimicrobial drugbacterial resistancebasecoastal watercostdesigndrug developmentfitnessimprovedinnovationinterestmembermicroorganism interactionnatural antimicrobialnovelpathogenpeptide synthasepublic health relevanceresistance mechanismsocialsuccesstraitwater sampling
项目摘要
DESCRIPTION (provided by applicant): Pathogenic, disease-causing Vibrio bacteria are persistent in U.S. coastal waters, as made evident by recurrent outbreaks originating from contaminated seafood or exposure to beaches. An extreme Vibrio cholerae outbreak occurred in Haiti after the 2010 catastrophic earthquake where 439,000 cases of cholera were reported, and over 6,200 deaths occurred. Previously, Haiti had been cholera free for over 100 years. Interestingly, Vibrio populations (i.e., closely related isolates that cluster as distinct phylogentic groups) sampled from the same coastal waters in the absence of an outbreak typically lack virulent strains, suggesting pathogenic vibrios have a decreased fitness at the population level. A likely but unexplored factor is the ability of other vibrios, belonging to non-pathogenic groups,
to synthesize compounds that antagonize nearby competitors, and likewise have the ability to resist such compounds. To this end, we propose to study antagonistic interactions among wild culturable marine bacteria using an established population-level approach under the hypothesis that pathogenic vibrios are outcompeted through population-wide interactions as a direct result of antimicrobial production by wild isolates. Preliminary results show we have identified wild strains that are capable of inhibiting growth of most other distantly related Vibrio within their proximal environment, but are themselves resistant; we refer to these isolates as 'Super Killers' (SKs). Seven SKs have been identified with differential activities and from multiple species. Here, we will 1) characterize the SK antimicrobial/resistance mechanisms, 2) investigate SK dynamics over time, and 3) test their ability to directly inhibit pathogens. We have developed and optimized a working genetic system for the manipulation of Vibrio environmental isolates (i.e., mutagenesis, gene deletions/insertions, and ectopic expression), such that we are able to efficiently identify and characterize the genetic loci involved in each compound's synthesis and corresponding resistance. In preliminary investigations with a single SK, we have identified a candidate genetic locus that encodes a putatively novel non-ribosomal peptide synthetase with antimicrobial function, and have begun to characterize the gene region and products, and associated resistance mechanism. This work has research merit in the identification of natural antimicrobial compounds and resistance mechanisms with the potential for new leads on drug development. The research plan has been designed in consideration of a high level of student involvement and training in an important and comprehensive study designed to characterize naturally occurring antimicrobial products and resistance mechanisms. The specific research itself offers much direct, hands-on involvement, using methodologies that are relatively straightforward, with little risk, and with a high likelihood of success. Finally, the project has been designed to impact student exposure to a range of topics (i.e., factors that influence pathogenicity, emergence of pathogens, antimicrobial compounds/resistance mechanisms, population-level interactions, etc.) and offers a smooth transition into a variety of biomedical interests.
描述(由申请人提供):致病性、致病性弧菌在美国沿海沃茨中持续存在,源于受污染海鲜或暴露于海滩的反复爆发证明了这一点。2010年海地发生灾难性地震后,发生了极端的霍乱弧菌疫情,报告了439,000例霍乱病例,6,200多人死亡。此前,海地已经100多年没有霍乱。有趣的是,弧菌种群(即,在没有爆发的情况下,从相同的沿海沃茨取样的聚集为不同的弧菌群的密切相关的分离物)通常缺乏毒性菌株,这表明致病性弧菌在种群水平上具有降低的适合度。一个可能但尚未探索的因素是属于非致病性群体的其他弧菌的能力,
合成对抗附近竞争者的化合物,并且同样具有抵抗这些化合物的能力。为此,我们建议研究野生可培养的海洋细菌之间的拮抗作用,使用一个既定的人口水平的方法下的假设,致病性弧菌被淘汰,通过人口范围内的相互作用作为一个直接结果的抗菌生产的野生菌株。初步结果表明,我们已经鉴定出能够抑制大多数其他远亲弧菌在其近端环境中生长的野生菌株,但它们本身具有抗性;我们将这些分离株称为“超级杀手”(SK)。已从多个物种中鉴定出具有不同活性的七种SK。在这里,我们将1)描述SK抗菌/耐药机制,2)研究SK随时间的动态变化,3)测试它们直接抑制病原体的能力。我们已经开发并优化了用于操纵弧菌环境分离株的工作遗传系统(即,诱变、基因缺失/插入和异位表达),使得我们能够有效地鉴定和表征参与每种化合物的合成和相应抗性的遗传基因座。在对单个SK的初步研究中,我们已经确定了一个编码具有抗菌功能的新型非核糖体肽合成酶的候选遗传位点,并已开始表征该基因区域和产物以及相关的耐药机制。这项工作在鉴定天然抗微生物化合物和耐药机制方面具有研究价值,具有药物开发新线索的潜力。该研究计划的设计考虑到了学生在一项重要而全面的研究中的高水平参与和培训,该研究旨在表征天然存在的抗菌产品和耐药性机制。具体的研究本身提供了很多直接的、亲身参与的机会,使用的方法相对简单,风险很小,成功的可能性很高。最后,该项目旨在影响学生接触一系列主题(即,影响致病性的因素、病原体的出现、抗微生物化合物/耐药性机制、群体水平的相互作用等)并提供了一个平稳过渡到各种生物医学的利益。
项目成果
期刊论文数量(1)
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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Hans Wildschutte其他文献
Hans Wildschutte的其他文献
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{{ truncateString('Hans Wildschutte', 18)}}的其他基金
Genetic basis of metabolite production against clinically-derived pathogens
针对临床衍生病原体的代谢产物产生的遗传基础
- 批准号:
10359347 - 财政年份:2018
- 资助金额:
$ 31.61万 - 项目类别:
Genetic basis of metabolite production against clinically-derived pathogens
针对临床衍生病原体的代谢产物产生的遗传基础
- 批准号:
10796488 - 财政年份:2018
- 资助金额:
$ 31.61万 - 项目类别:
Ecological Fitness of Vibrios and the Emergence of Pathogenic Traits
弧菌的生态适应性和致病性状的出现
- 批准号:
7486446 - 财政年份:2008
- 资助金额:
$ 31.61万 - 项目类别:
Ecological Fitness of Vibrios and the Emergence of Pathogenic Traits
弧菌的生态适应性和致病性状的出现
- 批准号:
7625019 - 财政年份:2008
- 资助金额:
$ 31.61万 - 项目类别:
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