Molecular Evolution of Resistance in Strep. pyogenes

描述（由申请方提供）：A组链球菌（GAS;化脓性链球菌）是高度流行的细菌病原体，感染人类咽喉或皮肤，引起咽炎或脓疱。GAS可引发自身免疫性疾病，如风湿热，或导致危及生命的感染，如中毒性休克综合征。GAS的大环内酯类耐药在20世纪80年代突然发展，并在20世纪90年代加速发展，在某些地区超过30%的GAS分离株。这项研究的长期目标是了解GAS中大环内酯类耐药的出现、传播和持续的分子机制。拟议中的研究以新颖的方式结合了流行病学，分子遗传学和基本进化原理。 目标1将寻求确定从世界各地收集的GAS大环内酯类耐药克隆的分子特征。使用核苷酸序列测定，将通过多位点序列分型确定emm型、耐药基因和管家基因座的分离株。将在因特网上维持一个数据库，以便利世界范围的监测。目标2将试图追踪新出现的抗性克隆的最近进化历史。进化模型可用于解决几个新问题：（a）估计耐药菌株出现的次数，（B）评估免疫逃逸在耐药基因传播中的重要性，（c）揭示多个耐药基因获得顺序的偏差，以及（d）根据其进化轨迹识别有问题的克隆和谱系。通过跟踪重组产生的核苷酸多态性，还将开发一种新的分子考古学方法，以预测世界抗性的哪些部分最有可能出现，以及克隆传播的地理路线。未来的研究可以完成所有大环内酯类耐药克隆的进化框架，扩展遗传动力学问题（a-d，上面），并评估外排与甲基化酶耐药机制的差异。 GAS在全球的高流行率，加上其高基因重组率，使其以意想不到的方式快速进化的时机已经成熟。GAS为理解抗生素耐药性出现和全球传播的早期阶段的分子进化提供了一个良好的模型系统。

DESCRIPTION (provided by applicant): Group A streptococci (GAS; Streptococcus pyogenes) are highly prevalent bacterial pathogens that infect the throat or skin of humans, causing pharyngitis or impetigo. GAS can trigger autoimmune disease, such as rheumatic fever, or cause life-threatening infections, such as toxic shock syndrome. Macrolide-resistance in GAS developed abruptly in the 1980s and accelerated in the 1990s, exceeding 30% of GAS isolates in some regions. The long-term goal of the proposed study is to understand the molecular mechanisms underlying the emergence, spread, and persistence of macrolideo resistance in GAS. The proposed research combines epidemiology, molecular genetics, and basic evolutionary principles in novel ways. Aim 1 will seek to define the molecular characteristics of macrolide-resistant clones of GAS collected from throughout the world. Using nucleotide sequence determination, isolates will be defined for emm-type, resistant genes and housekeeping loci, via multilocus sequence typing. A database will be maintained on the Internet, to facilitate worldwide surveillance. Aim 2 will seek to trace the recent evolutionary history of newly emerged resistant clones. Evolutionary models can be used to address several novel issues: (a) estimate the number of times resistant strains arose, (b) evaluate the significance of immune escape in the spread of resistance genes, (c) uncover bias in the order of acquisition of multiple resistance genes, and (d) identify problematic clones and lineages based on their evolutionary trajectory. By tracking nucleotide polymorphisms arising via recombination, a new molecular archaeological approach will also be developed, to predict which part(s) of the world resistance most likely emerged, and the geographical routes of clonal spread. Future studies can complete the evolutionary framework for all macrolide-resistant clones, extend the questions on genetic dynamics (a-d, above), and assess differences for efflux versus methylase resistance mechanisms. The high global prevalence of GAS, combined with its high rate of genetic recombination, makes it ripe for quickly evolving in unexpected ways. GAS provide a sound model system for understanding the molecular evolution underlying the early stages of the emergence and global spread of antibiotic resistance.