An integrated approach to understand the emergence and spread of extensively resistant Gram-negative bacteria in China

了解中国广泛耐药革兰氏阴性菌的出现和传播的综合方法

• 批准号: MR/P007597/1
• 负责人: Francois Balloux
• 金额: $ 108.09万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FP007597%2F1
• 关键词: integrated; approach; understand; emergence; spread

Since the discovery of penicillin in 1928 more than 100 antimicrobial agents have been identified and used to treat bacterial infections. This led to the near-eradication of some infectious diseases such as tuberculosis in the developed world. This advance in scientific discovery comes with a caveat, as microbes have acquired the ability to resist the toxic effects of these antimicrobial agents.The majority of bacteria that constitute antimicrobial threats are facultative, opportunistic pathogens which are found in great numbers in the environment and readily exchange genes with a variety of other microbes. Such elements include virulence factors, which allow them to infect animals and elude the host's immune system, and antimicrobial resistance genes that render them resistant to drugs. Over recent years, the biggest emerging antimicrobial resistance threat is represented by Gram-negative bacteria, which are increasingly breaching the last-resort drugs.With the advent of genome sequencing, we have learned a lot about the genes which make bacteria pathogenic and the ones that allow them to become resistant to drugs. However, we currently do not have the required computational tools to identify the routes through which "mobile elements" move between lineages of bacteria, or even quantify the extent of these exchanges. This in turn greatly limits our ability to block such transfer of resistance elements.We have assembled a multidisciplinary team to address three integrated issues. First, we will generate an extensive database of complete genomes of unprecedented quality for three major antimicrobial threats, Escherichia coli, Klebsiella pneumoniae and Acinetobacter baumannii. This will represent the first such high-quality microbial genomic database ever and will constitute a precious resource for the development of future diagnostic and prognostic tools. In a second step we will develop new computational tools to reconstruct the acquisition and spread of resistance in lineages of these three species in China. These tools will be flexible enough to be applied to genetic sequence data of any microbe and will allow us to reconstruct emergence and sread of resistance in these three species.Finally, we will perform functional validation in the lab to corroborate the findings from the bioinformatics and computational analyses. This work will also allow establishing the complex link between the genetic makeup of different lineages and their level of resistance to the three most important last-resort drugs carbapenem, tigecycline and colistin. The significance of this study lies in the multipronged approach to describe and characterise antimicrobial resistance in the most threatening Gram-negative bacteria in China. This effort will culminate in the identification of the key genetic and environmental factors that facilitate the proliferation and transmission of multi drug resistant pathogens. Such information should in turn lead to essential information on how to optimise antimicrobial stewardship both to the benefit of the patients and to stem the spread of resistance in the future.

自1928年发现青霉素以来，已有100多种抗菌剂被确定并用于治疗细菌感染。这导致发达国家几乎消灭了一些传染病，如肺结核。这一科学发现的进步伴随着一个警告，因为微生物已经获得了抵抗这些抗菌剂毒性作用的能力。构成抗菌素威胁的大多数细菌是兼性的、机会性的病原体，它们在环境中大量存在，并且很容易与各种其他微生物交换基因。这些因素包括使它们能够感染动物并避开宿主免疫系统的毒力因子，以及使它们具有耐药性的抗微生物基因。近年来，最大的新出现的抗菌素耐药性威胁是革兰氏阴性菌，它们越来越多地破坏最后的药物。随着基因组测序的出现，我们已经了解了很多关于使细菌致病的基因和使它们对药物产生抗药性的基因。然而，我们目前还没有必要的计算工具来确定“移动元素”在细菌谱系之间移动的路线，甚至量化这些交换的程度。这反过来又极大地限制了我们阻止这种阻力元素转移的能力。我们组建了一个多学科团队来解决三个综合问题。首先，我们将为大肠杆菌、肺炎克雷伯菌和鲍曼不动杆菌这三种主要的抗菌素威胁建立一个前所未有质量的广泛的全基因组数据库。这将是有史以来第一个如此高质量的微生物基因组数据库，并将为未来诊断和预后工具的开发提供宝贵的资源。第二步，我们将开发新的计算工具来重建这三个物种在中国的抗性获取和传播。这些工具将足够灵活，可以应用于任何微生物的基因序列数据，并将使我们能够重建这三个物种的耐药性的出现和传播。最后，我们将在实验室进行功能验证，以证实来自生物信息学和计算分析的发现。这项工作还将允许建立不同谱系的基因组成和它们对三种最重要的最后手段药物碳青霉烯、替加环素和粘菌素的抗性水平之间的复杂联系。这项研究的意义在于多管齐下的方法来描述和表征中国最具威胁性的革兰氏阴性菌的抗菌素耐药性。这一努力将最终确定促进多重耐药病原体增殖和传播的关键遗传和环境因素。这些信息应该反过来导致关于如何优化抗菌素管理的基本信息，以使患者受益并在未来阻止耐药性的传播。

项目成果

Q&A: What are pathogens, and what have they done to and for us?

• DOI: 10.1186/s12915-017-0433-z
• 发表时间: 2017-10-19
• 期刊: BMC biology
• 影响因子: 5.4
• 作者: Balloux F;van Dorp L
• 通讯作者: van Dorp L

Role of the mobilome in the global dissemination of the carbapenem resistance gene blaNDM

移动组在碳青霉烯类耐药基因 blaNDM 全球传播中的作用

• DOI: 10.21203/rs.3.rs-199409/v1
• 发表时间: 2021
• 作者: Acman M

From Theory to Practice: Translating Whole-Genome Sequencing (WGS) into the Clinic.

• DOI: 10.1016/j.tim.2018.08.004
• 发表时间: 2018-12
• 期刊: Trends in microbiology
• 影响因子: 15.9
• 作者: Balloux F;Brønstad Brynildsrud O;van Dorp L;Shaw LP;Chen H;Harris KA;Wang H;Eldholm V
• 通讯作者: Eldholm V

Global expansion of Mycobacterium tuberculosis lineage 4 shaped by colonial migration and local adaptation.

结核分枝杆菌谱系4的全球扩展，由殖民地迁移和局部适应。

• DOI: 10.1126/sciadv.aat5869
• 发表时间: 2018-10
• 期刊: Science advances
• 影响因子: 13.6
• 作者: Brynildsrud OB;Pepperell CS;Suffys P;Grandjean L;Monteserin J;Debech N;Bohlin J;Alfsnes K;Pettersson JO;Kirkeleite I;Fandinho F;da Silva MA;Perdigao J;Portugal I;Viveiros M;Clark T;Caws M;Dunstan S;Thai PVK;Lopez B;Ritacco V;Kitchen A;Brown TS;van Soolingen D;O'Neill MB;Holt KE;Feil EJ;Mathema B;Balloux F;Eldholm V
• 通讯作者: Eldholm V

Large-scale network analysis captures biological features of bacterial plasmids

大规模网络分析捕获细菌质粒的生物学特征

• DOI: 10.1101/785212
• 发表时间: 2019
• 作者: Acman M