Plasmids as Vectors of Antibiotic Resistance: The Evolution of Plasmid Host-Range

作为抗生素抗性载体的质粒：质粒宿主范围的进化

• 批准号: 8259843
• 负责人: Zaid Abdo
• 金额: $ 34.76万
• 依托单位: UNIVERSITY OF IDAHO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8259843
• 关键词: Address; Affect; Antibiotic Resistance; Antibiotics; Bacteria; Centers for Disease Control and Prevention (U.S.); Communicable Diseases; Complex; Data; Development; Drug Formulations; Drug resistance; Evolution; Future; Gene Transfer; Genes; Genetic Determinism; Genotype; Goals; Health; Hot Spot; Human; In Vitro; Knowledge; Lead; Mediating; Medical; Methods; Modeling; Molecular; Multi-Drug Resistance; Mutagenesis; Mutation; Pattern; Pharmacotherapy; Phenotype; Plasmids; Point Mutation; Population; Proteins; Pseudomonas aeruginosa; Public Health; Recording of previous events; Replicon; Reporting; Research; Research Support; Resistance; Role; Sequence Analysis; Statistical Models; Time; Variant; Virulence; Work; base; cost; disorder prevention; fight against; fitness; genetic element; genome sequencing; improved; infectious disease treatment; insight; interest; mathematical model; models and simulation; novel; pathogen; pathogenic bacteria; public health relevance; research study; simulation; vector

DESCRIPTION (provided by applicant): Plasmids as Vectors of Antibiotic Resistance: Evolution of Plasmid Host Range The dramatic spread of antibiotic resistance is a crisis in the treatment of infectious diseases that affect humans. Although plasmid-mediated gene transfer is now recognized as an important means for the spread of drug resistance, very little is known about the range of hosts to which plasmids can transfer, or if this range evolves over time. While some plasmids only transfer and stably replicate in a narrow range of hosts, so-called broad-host-range plasmids can transfer and replicate in distantly related bacteria, thereby shuffling resistance genes across taxonomic barriers. Understanding the features of the broad-host-range plasmids responsible for their ability to function in a wide range of bacterial hosts is therefore of both medical and fundamental interest. The research proposed builds on and extends the findings of previous studies, which showed that various mutations in the plasmid encoded Rep protein (TrfA) required for plasmid replication are sufficient to alter the host range of a broad-host-range (BHR) plasmid. The long-term goal of this project is to gain insight into the evolutionary patterns of host range shifts of drug resistance plasmids. Here we will explore the general mechanisms and dynamics of plasmid host range evolution by integrating data from experimental evolution of BHR and narrow host range (NHR) plasmids with statistical modeling of plasmid evolutionary dynamics. In this multi-disciplinary study, we propose to address the following specific aims: (1) Determine the evolutionary mechanisms of host range shifts by BHR and NHR plasmids; (2) Develop statistical models and simulations of plasmid evolutionary dynamics; (3) Determine the molecular mechanisms of plasmid host range shifts. In the future, this fundamental knowledge will support research into drug therapies based on restricting the horizontal transfer or stable replication of drug resistance or virulence plasmids in human pathogens. Restricting the spread and persistence of unwanted plasmids is a novel and promising avenue in the fight against human pathogens that could very well be part of future strategies to avoid escalation of this health crisis. PUBLIC HEALTH RELEVANCE: This work will provide a roadmap for further mechanistic studies on the role of specific mutations in plasmid host-range and may lead to attractive therapies that target the replication of antibiotic resistance plasmids and limit the spread of antibiotic resistance in human pathogens.

描述（由申请人提供）：作为抗生素抗性载体的质粒：质粒宿主范围的进化抗生素抗性的急剧蔓延是影响人类的传染病治疗中的危机。尽管质粒介导的基因转移现在被认为是传播耐药性的重要手段，但人们对质粒可以转移的宿主范围或该范围是否随着时间的推移而演变知之甚少。虽然一些质粒只能在狭窄的宿主范围内转移和稳定复制，但所谓的广泛宿主范围质粒可以在亲缘关系较远的细菌中转移和复制，从而跨越分类障碍改变抗性基因。因此，了解广泛宿主范围质粒的特征及其在多种细菌宿主中发挥作用的能力，具有医学和根本意义。这项研究建立在并扩展了之前的研究结果的基础上，这些研究表明，质粒复制所需的质粒编码的 Rep 蛋白 (TrfA) 中的各种突变足以改变广宿主范围 (BHR) 质粒的宿主范围。该项目的长期目标是深入了解耐药质粒宿主范围转变的进化模式。在这里，我们将通过将 BHR 和窄宿主范围 (NHR) 质粒的实验进化数据与质粒进化动力学的统计模型相结合，探索质粒宿主范围进化的一般机制和动力学。在这项多学科研究中，我们建议解决以下具体目标：（1）确定BHR和NHR质粒宿主范围转移的进化机制； (2) 开发质粒进化动力学的统计模型和模拟； (3)确定质粒宿主范围转移的分子机制。未来，这一基础知识将支持基于限制人类病原体中耐药性或毒力质粒的水平转移或稳定复制的药物治疗研究。限制不需要的质粒的传播和持续存在是对抗人类病原体的一种新颖且有前途的途径，这很可能成为避免这场健康危机升级的未来战略的一部分。 公共卫生相关性：这项工作将为进一步研究质粒宿主范围内特定突变的作用提供路线图，并可能带来有吸引力的治疗方法，以抗生素耐药性质粒的复制为目标，并限制抗生素耐药性在人类病原体中的传播。