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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：
Travis J Wiles
金额：
$ 8.12万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
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：
https://reporter.nih.gov/project-details/10830636
关键词：
Address Affect Agriculture Animals Antibiotic Resistance Antibiotics Architecture Attention Bacteria Bacterial Antibiotic Resistance Bacteriophages Behavior Biological Models Cell physiology Cells Ciprofloxacin Collection Combating Antibiotic Resistant Bacteria Complex DNA Damage Disease Dissociation Dose Ecology Ecosystem Elements Environment Environmental Risk Factor Evolution Food Supply Future Genetic Genetic Engineering Health Horizontal Gene Transfer Human Image In Situ In Vitro Individual Infection Intestines Livestock Memory Methods Microbe Mobile Genetic Elements Modeling Molecular Motivation Movement Mus Mutation Nature Optics Pathway interactions Personal Satisfaction Pharmaceutical Preparations Physical shape Physiological Physiology Plasmids Production Reporter Research Resistance Resolution SOS Response Signal Pathway Structure Swimming System Testing Therapeutic Time Tissues Work Zebrafish bacterial community bacterial resistance cell motility de novo mutation design drug development experimental study fighting genetic manipulation gut bacteria gut microbiome innovation microbial microbiota molecular scale novel pathogen preservation prevent public health intervention resistance gene response side effect spatiotemporal synthetic biology tool trait transmission 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.

项目总结抗药性细菌对人类的健康和福祉构成全球威胁。新的战略抗击耐药性是当务之急，因为目前的药物开发管道跟不上随着有效抗生素供应的减少。我建议调查和操纵地球的生态抗生素耐药性的获得和宿主到宿主的传播。具体地说，我将确定如何在物理上肠道内细菌群落的结构--这是抗生素耐药性的主要储存库细菌--影响耐药特性的进化和耐药细胞的传播。这是一种动机研究方向是抗生素耐药性从根本上取决于空间和时间寄主-微生物系统的组织。例如，细菌之间的抗药性基因共享通过横向基因转移通常要求细胞彼此靠近。此外，耐药细菌在宿主之间的传播需要它们被物理置换并被驱逐到环境。因此，可以使用改变肠道细菌群落的时空组织在耐药细菌成为感染剂之前预防和遏制它们。然而，剖析管理抗生素耐药性的时空复杂机制是一个重大挑战，使用目前的方法。我克服这一局限的解决方案是将合成生物学与遗传学相结合工程设计的细菌群落，以及实时成像来跟踪和控制细菌在活体动物的肠道。我将使用幼虫斑马鱼作为脊椎动物的宿主模型，因为它们能够对宿主-微生物系统的研究，跨越复杂性、空间和时间的尺度，很难在无论是老鼠还是人类。使用这种实验方法，我之前发现肠道流动，细菌游泳动力和亚致命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生理格局。我会驾驭这些因素和我的实验方法解决了以下三个假设。首先，我将测试假设肠道细菌的时空组织控制着肠道细菌的获得和持久性肠道内的耐药性特征。其次，我将检验这样一种假设，即肠道细菌调节耐药细胞在宿主之间的传播。第三，我将测试细菌协调获得抗性特征和宿主到宿主传播的假说通过特定的遗传途径。我提出的研究有可能启发基于生态学的通过肠道治疗性操作减少抗生素耐药性的策略微生物组的物理结构。这种生态知情和不含抗生素的策略将保护在最需要的时候发挥当前抗生素的效力，并避免抗生素对有益的常驻细菌。