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

描述（申请人提供）：质粒作为抗生素耐药性的载体：质粒宿主范围的进化抗生素耐药性的急剧蔓延是影响人类的传染病治疗中的危机。虽然质粒介导的基因转移现在被认为是耐药性传播的重要手段，但对质粒可以转移的宿主范围或该范围是否随时间推移而演变知之甚少。虽然一些质粒仅在窄范围的宿主中转移和稳定复制，但所谓的宽宿主范围质粒可以在远亲细菌中转移和复制，从而使耐药基因跨越分类障碍。因此，了解负责其在广泛的细菌宿主中发挥作用的能力的广宿主范围质粒的特征具有医学和根本利益。这项研究建立在并扩展了以前研究的发现，这些研究表明，质粒复制所需的质粒编码Rep蛋白（TrfA）中的各种突变足以改变宽宿主范围（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移的进化模式。在这里，我们将探索质粒宿主范围进化的一般机制和动力学整合数据从实验进化BHR和窄宿主范围（NHR）质粒与质粒进化动力学的统计建模。在这项多学科研究中，我们提出了以下具体目标：（1）确定BHR和NHR质粒宿主范围转移的进化机制;（2）建立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。在未来，这些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疗法研究。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个新的和有前途的途径，很可能成为未来避免这一健康危机升级的战略的一部分。 公共卫生相关性：这项工作将为进一步研究质粒宿主范围中特定突变的作用机制提供路线图，并可能导致有吸引力的治疗方法，靶向抗生素耐药质粒的复制，并限制抗生素耐药性在人类病原体中的传播。

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.