Connecting the Spatiotemporal Organization of Gut Bacterial Communities to the Emergence and Spread of Antibiotic Resistance
将肠道细菌群落的时空组织与抗生素耐药性的出现和传播联系起来
基本信息
- 批准号:10830636
- 负责人:
- 金额:$ 8.12万
- 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:2021-05-05 至 2026-04-30
- 项目状态:未结题
- 来源:
- 关键词:AddressAffectAgricultureAnimalsAntibiotic ResistanceAntibioticsArchitectureAttentionBacteriaBacterial Antibiotic ResistanceBacteriophagesBehaviorBiological ModelsCell physiologyCellsCiprofloxacinCollectionCombating Antibiotic Resistant BacteriaComplexDNA DamageDiseaseDissociationDoseEcologyEcosystemElementsEnvironmentEnvironmental Risk FactorEvolutionFood SupplyFutureGeneticGenetic EngineeringHealthHorizontal Gene TransferHumanImageIn SituIn VitroIndividualInfectionIntestinesLivestockMemoryMethodsMicrobeMobile Genetic ElementsModelingMolecularMotivationMovementMusMutationNatureOpticsPathway interactionsPersonal SatisfactionPharmaceutical PreparationsPhysical shapePhysiologicalPhysiologyPlasmidsProductionReporterResearchResistanceResolutionSOS ResponseSignal PathwayStructureSwimmingSystemTestingTherapeuticTimeTissuesWorkZebrafishbacterial communitybacterial resistancecell motilityde novo mutationdesigndrug developmentexperimental studyfightinggenetic manipulationgut bacteriagut microbiomeinnovationmicrobialmicrobiotamolecular scalenovelpathogenpreservationpreventpublic health interventionresistance generesponseside effectspatiotemporalsynthetic biologytooltraittransmission process
项目摘要
PROJECT SUMMARY
Antibiotic resistant bacteria pose a global threat to human health and wellbeing. New strategies for
combating resistance are urgently needed because current drug development pipelines are not keeping up
with the dwindling supply of effective antibiotics. I propose to investigate and manipulate the ecology of
antibiotic resistance acquisition and host-to-host transmission. Specifically, I will determine how the physical
structure of bacterial communities within the intestine—which is a major reservoir of antibiotic resistant
bacteria—affects the evolution of resistance traits and transmission of resistant cells. A motivation for this
research direction is that antibiotic resistance fundamentally dependends on the spatial and temporal
organization of host–microbe systems. For example, the sharing of resistance genes between bacteria
through lateral gene transfer often requires cells to be in close proximity to one another. In addition, the
transmission of resistant bacteria between hosts requires that they are physically displaced and expelled into
the environment. Thus, altering the spatiotemporal organization of gut bacterial communities could be used
to prevent and contain resistant bacteria before they become agents of infection. However, dissecting the
spatially and temporally complex mechanisms governing antibiotic resistance is a significant challenge using
current approaches. My solution to overcome this limitation is to combine synthetic biology, genetically
engineered bacterial communities, and live imaging to track and control bacterial behavior inside the
intestines of living animals. I will employ larval zebrafish as a vertebrate host model because they enable
studies of host–microbe systems across scales of complexity, space, and time that are difficult to perform in
mice or humans. Using this experimental approach, I previously discovered that intestinal flow, bacterial
swimming motility, and sublethal antibiotics represent host, bacterial, and environmental factors, respectively,
that can modulate the spatiotemporal organization and physiological landscape of gut bacteria. I will harness
these factors and my experimental approach to address the following three hypotheses. First, I will test the
hypothesis that the spatiotemporal organization of gut bacteria controls the acquisition and persistence of
resistance traits within the intestine. Second, I will test the hypothesis that the spatiotemporal organization of
gut bacteria regulates the transmission of antibiotic resistant cells between hosts. And third, I will test the
hypothesis that bacteria coordinate both the acquisition of resistance traits and host-to-host transmission
through specific genetic pathways. My proposed research has the potential to inspire ecology-based
strategies for curtailing antibiotic resistance through the therapeutic manipulation of the intestinal
microbiome’s physical structure. Such ecology-informed and antibiotic-free strategies would preserve the
potency of current antibiotics for when they are needed most and avoid the unintended side effects of
antibiotics on beneficial resident bacteria.
项目摘要
抗生素耐药细菌对人类健康和福祉构成了全球威胁。新的策略
由于目前的药物开发管道无法跟上,因此迫切需要打击抵抗力
随着有效抗生素的供应减少。我建议调查和操纵
抗生素耐药性获取和宿主到宿主传播。具体来说,我将确定身体
肠内细菌群落的结构 - 这是抗生素抗性的主要优质者
细菌 - 影响抗性性状的演变和抗性细胞的传播。为此的动力
研究方向是抗生素耐药性从根本上取决于空间和临时性
宿主 - 微型系统的组织。例如,细菌之间的耐药基因共享
通过横向基因转移通常要求细胞彼此近距离接近。另外,
宿主之间抗性细菌的传播要求它们物理位移并排出
环境。这可以使用肠道细菌群落的空间临时组织
在成为感染的药物之前预防并含有抗性细菌。但是,解剖
在空间和临时复杂的机制中,抗生素耐药性是一个重大挑战
当前的方法。我克服这一限制的解决方案是将合成生物学结合起来
设计的细菌群落和实时成像以跟踪和控制细菌行为
活动物的肠道。我将使用幼虫斑马鱼作为脊椎动物宿主模型,因为它们启用了
跨越复杂性,空间和时间的宿主 - 微型系统的研究,难以执行
老鼠或人类。使用这种实验方法,我先前发现了肠流,细菌
游泳运动和全抗生素分别代表宿主,细菌和环境因素
这可以调节肠道细菌的时空组织和物理景观。我会用
这些因素和我解决以下三个假设的实验方法。首先,我将测试
假设肠道细菌的时空组织控制着的获取和持久性
肠内的阻力特征。其次,我将检验以下假设
肠道细菌调节宿主之间抗生素耐药细胞的传播。第三,我将测试
假设细菌均协调抗药性性状和宿主传播的辅助
通过特定的遗传途径。我提出的研究有可能激发基于生态的基础
通过对肠道的治疗操纵来减少抗生素抗性的策略
微生物组的物理结构。这种生态信息和无抗生素的策略将保留
当前抗生素的效力最需要何时需要
关于有益居住细菌的抗生素。
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)
Cultivating Healthy Connections: Exploring and Engineering the Microbial Flow That Shapes Microbiomes.
- DOI:10.1128/msystems.00863-21
- 发表时间:2021-10-26
- 期刊:
- 影响因子:6.4
- 作者:Wiles TJ
- 通讯作者:Wiles TJ
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{{ truncateString('Travis J Wiles', 18)}}的其他基金
Connecting the Spatiotemporal Organization of Gut Bacterial Communities to the Emergence and Spread of Antibiotic Resistance
将肠道细菌群落的时空组织与抗生素耐药性的出现和传播联系起来
- 批准号:
10401754 - 财政年份:2021
- 资助金额:
$ 8.12万 - 项目类别:
Connecting the Spatiotemporal Organization of Gut Bacterial Communities to the Emergence and Spread of Antibiotic Resistance
将肠道细菌群落的时空组织与抗生素耐药性的出现和传播联系起来
- 批准号:
10051053 - 财政年份:2021
- 资助金额:
$ 8.12万 - 项目类别:
Connecting the Spatiotemporal Organization of Gut Bacterial Communities to the Emergence and Spread of Antibiotic Resistance
将肠道细菌群落的时空组织与抗生素耐药性的出现和传播联系起来
- 批准号:
10608117 - 财政年份:2021
- 资助金额:
$ 8.12万 - 项目类别:
Elucidation of Host and Bacterial Factors that Influence Resilience and Robustnes
影响弹性和鲁棒性的宿主和细菌因素的阐明
- 批准号:
8823468 - 财政年份:2014
- 资助金额:
$ 8.12万 - 项目类别:
Elucidation of Host and Bacterial Factors that Influence Resilience and Robustnes
影响弹性和鲁棒性的宿主和细菌因素的阐明
- 批准号:
8716351 - 财政年份:2014
- 资助金额:
$ 8.12万 - 项目类别:
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