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：
Yonatan H Grad
金额：
$ 47.85万
依托单位：
HARVARD SCHOOL OF PUBLIC HEALTH
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

来源：
https://reporter.nih.gov/project-details/10736734
关键词：
Acceleration Address Antibiotic Resistance Antibiotic susceptibility Antibiotics Antimicrobial Resistance Australia Bacteria Bacterial Antibiotic Resistance Bacterial Physiology Bar Codes Biology Candidate Disease Gene Case Study Ceftriaxone Ciprofloxacin Clinical Clinical Management Complex Data Data Set Development Drug Binding Site Drug Exposure Drug Targeting Drug resistance Epidemiologic Monitoring Europe Evolution Genes Genetic Genetic Determinism Genome Genomic approach Genotype Goals Gonorrhea In Vitro Infection Knowledge Libraries Link Literature Maintenance Metabolic Methods Molecular Multi-Drug Resistance Mutagenesis Mutation Nature Neisseria gonorrhoeae Pathway interactions Pharmaceutical Preparations Phenotype Phylogenetic Analysis Phylogeny Population Population Genetics Population Surveillance Predisposition Prevalence Public Health Publishing Rapid diagnostics Recommendation Reporting Resistance Resistance development Risk Sampling Sexually Transmitted Diseases Specificity Support Groups System Testing Therapeutic United States Variant Work acquired drug resistance antimicrobial burden of illness candidate identification candidate validation clinically relevant cost fitness genetic resistance genomic locus genomic tools high risk improved innovation large datasets novel novel strategies pathogen pathogenic bacteria phase III trial prevent resistance mechanism resistant strain support network tool

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.

项目摘要/摘要抗生素耐药细菌的兴起对公共卫生构成了严重威胁。胜任易感性细菌和患病率的增加，抗性菌株必须减轻抗性产生的适应性成本 - 赋予突变和基因。但是，并非细菌物种的每种菌株都可以获取和维持抗药性的遗传决定因素同样很好，从而产生了复杂的进化景观敏感性和抵抗力。阐明支持获取的机制的性质和多样性维持抵抗力将使我们能够了解耐药应力如何出现和传播以及从而加快迫切需要的新策略来预防和治疗抗药性的新策略感染。我们专注于临床上重要的病原体淋病奈瑟氏菌（The Gonocococcus），鉴于其高负担疾病（2021年在美国报道了近700,000例），迫在眉睫的感染威胁和实验操作的便利性。我们的目标是定义支持获取和维持对淋病乳杆菌治疗临床上最重要的抗生素的耐药性：最后批准的抗生素，头孢曲松；环丙沙星，为此，批准了用于定向治疗的快速诊断。欧洲;以及第三阶段试验中的两种药物，佐洛飞去了和gepotidacin。为此，我们将利用数据集其中包括约18,000个临床分离株和文库的基因组序列和抗生素敏感性谱代表物种多样性的数百个选定的临床分离株。我们将使用计算和实验方法，包括种群遗传学和统计工具，以鉴定亚遗传学差异人口；高通量杆编码的库和实验进化，以定义影响的基因座抗药性作为遗传背景的函数；基因组操纵以验证之间的联系基因型和抗性表型；和机械研究以阐明这些遗传基因座如何影响敏感性和抵抗力之间的健身景观。我们预计这些研究的结果将定义有助于在淋病链球菌中获得和维持对抗生素最高临床重要性的抗药性。这些结果可以应用于改善临床管理策略和公共卫生监视努力。此外，我们在这里建立的系统可用于进一步探测淋病乳杆菌的生物学并为开发类似系统的开发提供了一个框架以剖析抗药性的遗传网络在其他细菌病原体中。

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）

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。

DOI：
10.1016/j.trsl.2020.02.002
发表时间：
2020
期刊：
Translational research : the journal of laboratory and clinical medicine
影响因子：
0
作者：
Rubin,DanielHF;Ross,JonathanDC;Grad,YonatanH
通讯作者：
Grad,YonatanH

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：
mBio
影响因子：
6.4
作者：
通讯作者：

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：
The Lancet. Infectious diseases
影响因子：
0
作者：
Whittles,LilithK;Didelot,Xavier;Grad,YonatanH;White,PeterJ
通讯作者：
White,PeterJ

The Distribution and Spread of Susceptible and Resistant Neisseria gonorrhoeae Across Demographic Groups in a Major Metropolitan Center.

DOI：
10.1093/cid/ciaa1229
发表时间：
2021-11-02
期刊：
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
影响因子：
0
作者：
Mortimer TD;Pathela P;Crawley A;Rakeman JL;Lin Y;Harris SR;Blank S;Schillinger JA;Grad YH
通讯作者：
Grad YH

Deciphering the Impact of Bystander Selection for Antibiotic Resistance in Neisseria gonorrhoeae.

解读旁观者选择对淋病奈瑟菌抗生素耐药性的影响。