Genomics approaches to elucidating pathways to antibiotic resistance in Neisseria gonorrhoeae

阐明淋病奈瑟菌抗生素耐药性途径的基因组学方法

基本信息

  • 批准号:
    10736734
  • 负责人:
  • 金额:
    $ 47.85万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2017
  • 资助国家:
    美国
  • 起止时间:
    2017-07-01 至 2028-05-31
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY/ABSTRACT The rise of antibiotic resistant bacteria poses a grave threat to public health. To outcompete susceptible bacteria and increase in prevalence, resistant strains must mitigate fitness costs incurred by resistance- conferring mutations and genes. However, not every strain of a bacterial species can acquire and maintain genetic determinants of resistance equally well, yielding a complex evolutionary landscape between susceptibility and resistance. Elucidating the nature and diversity of the mechanisms that support acquisition and maintenance of resistance will allow us to understand how resistant strains emerge and spread and thereby accelerate development of desperately needed new strategies to prevent and treat resistant infections. We focus on the clinically important pathogen Neisseria gonorrhoeae (the gonococcus), given its high burden of disease (nearly 700,000 reported cases in the US in 2021), the imminent threat of untreatable infection, and the ease of experimental manipulation. Our goal is to define the genetic networks that support acquisition and maintenance of resistance to the most clinically important antibiotics for N. gonorrhoeae treatment: the last approved antibiotic, ceftriaxone; ciprofloxacin, for which rapid diagnostics for directed therapy are approved in Europe; and the two drugs in Phase 3 trials, zoliflodacin and gepotidacin. To do so, we will leverage a dataset that includes genome sequences and antibiotic susceptibility profiles for ~18,000 clinical isolates and a library of hundreds of selected clinical isolates, representing the species diversity. We will use computational and experimental methods, including population genetics and statistical tools to identify genetic differences in sub- populations; high-throughput bar-coded library and experimental evolution to define the loci that impact resistance acquisition as a function of genetic background; genome manipulation to validate links between genotype and resistance phenotype; and mechanistic studies to elucidate how these genetic loci influence the fitness landscape between susceptibility and resistance. We expect that the results from these studies will define the stepping-stone mutations that contribute to acquisition and maintenance of resistance to the antibiotics of highest clinical importance in N. gonorrhoeae. These results can be applied to improving clinical management strategies and public health surveillance efforts. Moreover, the system we establish here can be used to further probe the biology of N. gonorrhoeae and provides a framework for the development of similar systems to dissect the genetic networks of resistance in other bacterial pathogens.
项目总结/摘要 抗生素耐药性细菌的增加对公众健康构成严重威胁。在竞争中战胜易受影响的 细菌和流行率的增加,耐药菌株必须减轻耐药引起的健康成本- 赋予突变和基因。然而,并非每种细菌都能获得并维持 抗性的遗传决定因素同样好,产生了一个复杂的进化景观之间 易感性和耐药性。阐明支持获取的机制的性质和多样性 和维持耐药性将使我们了解耐药菌株是如何产生和传播的, 从而加速开发迫切需要的新战略, 感染. 我们重点关注临床上重要的病原体淋病奈瑟菌(淋球菌),鉴于其高负担 疾病(2021年美国报告近70万例),无法治愈的感染的迫在眉睫的威胁,以及 实验操作的简易性我们的目标是定义支持获得的遗传网络, 维持耐药性的最重要的临床抗生素的N。淋病治疗:最后 批准的抗生素,头孢曲松;环丙沙星,用于定向治疗的快速诊断被批准, 欧洲;以及3期试验中的两种药物,zoliflodacin和gepotidacin。为此,我们将利用数据集 包括约18,000个临床分离株的基因组序列和抗生素敏感性谱以及一个文库 数百种临床分离株,代表了物种多样性。我们将使用计算和 实验方法,包括人口遗传学和统计工具,以确定遗传差异的亚, 群体;高通量条形码文库和实验进化,以确定影响 抗性获得作为遗传背景的函数;基因组操作以验证 基因型和抗性表型;以及阐明这些遗传位点如何影响抗性的机制研究。 易感性和抗性之间的适应度景观。 我们希望这些研究的结果将确定有助于 获得和维持耐药性的抗生素最高的临床重要性,在N。淋病 这些结果可用于改进临床管理策略和公共卫生监测 努力此外,我们建立的系统可用于进一步探讨N.淋病 并为类似系统的开发提供了一个框架, 其他细菌病原体。

项目成果

期刊论文数量(25)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Sculpting the Bacterial O-Glycoproteome: Functional Analyses of Orthologous Oligosaccharyltransferases with Diverse Targeting Specificities.
  • DOI:
    10.1128/mbio.03797-21
  • 发表时间:
    2022-06-28
  • 期刊:
  • 影响因子:
    6.4
  • 作者:
  • 通讯作者:
The frontiers of addressing antibiotic resistance in Neisseria gonorrhoeae.
解决淋病奈瑟菌抗生素耐药性的前沿。
The Distribution and Spread of Susceptible and Resistant Neisseria gonorrhoeae Across Demographic Groups in a Major Metropolitan Center.
Testing for gonorrhoea should routinely include the pharynx.
淋病检查应常规包括咽部检查。
  • DOI:
    10.1016/s1473-3099(18)30341-4
  • 发表时间:
    2018
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Whittles,LilithK;Didelot,Xavier;Grad,YonatanH;White,PeterJ
  • 通讯作者:
    White,PeterJ
Estimating the fitness cost and benefit of antimicrobial resistance from pathogen genomic data.
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Yonatan H Grad其他文献

emNeisseria gonorrhoeae/em diagnostic escape from a emgyrA/em-based test for ciprofloxacin susceptibility and the effect on zoliflodacin resistance: a bacterial genetics and experimental evolution study
淋病奈瑟菌对基于 gyrA 的环丙沙星敏感性检测的诊断逃逸及对唑立复林耐药性的影响:一项细菌遗传学和实验进化研究
  • DOI:
    10.1016/s2666-5247(22)00356-1
  • 发表时间:
    2023-04-01
  • 期刊:
  • 影响因子:
    20.400
  • 作者:
    Daniel HF Rubin;Tatum D Mortimer;Yonatan H Grad
  • 通讯作者:
    Yonatan H Grad
Modelling molecular and culture-based surveillance of tetracycline resistance in emNeisseria gonorrhoeae/em
淋病奈瑟菌四环素耐药性基于分子和培养的监测模型
  • DOI:
    10.1016/s1473-3099(24)00408-0
  • 发表时间:
    2024-08-01
  • 期刊:
  • 影响因子:
    31.000
  • 作者:
    Kirstin I Oliveira Roster;Rachel Mittelstaedt;Jordan Reyes;Aishani V Aatresh;Yonatan H Grad
  • 通讯作者:
    Yonatan H Grad
Trends in infection incidence and antimicrobial resistance in the US Veterans Affairs Healthcare System: a nationwide retrospective cohort study (2007–22)
美国退伍军人事务医疗保健系统感染发生率和抗菌药物耐药性趋势:一项全国性回顾性队列研究(2007-22 年)
  • DOI:
    10.1016/s1473-3099(24)00416-x
  • 发表时间:
    2024-12-01
  • 期刊:
  • 影响因子:
    31.000
  • 作者:
    Thi Mui Pham;Yue Zhang;McKenna Nevers;Haojia Li;Karim Khader;Yonatan H Grad;Marc Lipsitch;Matthew Samore
  • 通讯作者:
    Matthew Samore
Biodiversity and hypervirulence of Listeria monocytogenes
单核细胞增生李斯特菌的生物多样性和超强毒性
  • DOI:
    10.1038/ng.3515
  • 发表时间:
    2016-02-24
  • 期刊:
  • 影响因子:
    29.000
  • 作者:
    Yonatan H Grad;Sarah M Fortune
  • 通讯作者:
    Sarah M Fortune

Yonatan H Grad的其他文献

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{{ truncateString('Yonatan H Grad', 18)}}的其他基金

Genetic modulators of serum resistance in Neisseria gonorrhoeae
淋病奈瑟菌血清抗性的遗传调节剂
  • 批准号:
    10608700
  • 财政年份:
    2023
  • 资助金额:
    $ 47.85万
  • 项目类别:
Identification and analysis of compensatory mutations that support the evolution of antibiotic resistance in Neisseria gonorrhoeae
支持淋病奈瑟菌抗生素耐药性进化的补偿突变的鉴定和分析
  • 批准号:
    10443593
  • 财政年份:
    2020
  • 资助金额:
    $ 47.85万
  • 项目类别:
Identification and analysis of compensatory mutations that support the evolution of antibiotic resistance in Neisseria gonorrhoeae
支持淋病奈瑟菌抗生素耐药性进化的补偿突变的鉴定和分析
  • 批准号:
    10034093
  • 财政年份:
    2020
  • 资助金额:
    $ 47.85万
  • 项目类别:
Identification and analysis of compensatory mutations that support the evolution of antibiotic resistance in Neisseria gonorrhoeae
支持淋病奈瑟菌抗生素耐药性进化的补偿突变的鉴定和分析
  • 批准号:
    10219082
  • 财政年份:
    2020
  • 资助金额:
    $ 47.85万
  • 项目类别:
Identification and analysis of compensatory mutations that support the evolution of antibiotic resistance in Neisseria gonorrhoeae
支持淋病奈瑟菌抗生素耐药性进化的补偿突变的鉴定和分析
  • 批准号:
    10650744
  • 财政年份:
    2020
  • 资助金额:
    $ 47.85万
  • 项目类别:
Genomics approaches to elucidating pathways to antibiotic resistance in Neisseria gonorrhoeae
阐明淋病奈瑟菌抗生素耐药性途径的基因组学方法
  • 批准号:
    9367004
  • 财政年份:
    2017
  • 资助金额:
    $ 47.85万
  • 项目类别:
Genomics approaches to elucidating pathways to antibiotic resistance in Neisseria gonorrhoeae
阐明淋病奈瑟菌抗生素耐药性途径的基因组学方法
  • 批准号:
    10190792
  • 财政年份:
    2017
  • 资助金额:
    $ 47.85万
  • 项目类别:
Genomic epidemiology of Neisseria gonorrhoeae with elevated MICs to cefixime
头孢克肟 MIC 升高的淋病奈瑟菌的基因组流行病学
  • 批准号:
    8862369
  • 财政年份:
    2013
  • 资助金额:
    $ 47.85万
  • 项目类别:
Genomic epidemiology of Neisseria gonorrhoeae with elevated MICs to cefixime
头孢克肟 MIC 升高的淋病奈瑟菌的基因组流行病学
  • 批准号:
    9005937
  • 财政年份:
    2013
  • 资助金额:
    $ 47.85万
  • 项目类别:
Genomic epidemiology of Neisseria gonorrhoeae with elevated MICs to cefixime
头孢克肟 MIC 升高的淋病奈瑟菌的基因组流行病学
  • 批准号:
    8487485
  • 财政年份:
    2013
  • 资助金额:
    $ 47.85万
  • 项目类别:

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