Canada_IPAP Antimicrobial-resistant Enterococcus faecium in the One Health context in the UK and Canada

Canada_IPAP 英国和加拿大 One Health 背景下的耐药屎肠球菌

• 批准号: BB/X012727/1
• 负责人: Sharon Peacock
• 金额: $ 19.09万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FX012727%2F1
• 关键词: Canada_IPAP; Antimicrobial; resistant; Enterococcus; faecium

Antimicrobial resistance is one of the greatest public health threats spanning the One Health continuum (humans, animals and the environment). Antibiotics are of invaluable public health importance and are used on a daily basis worldwide to save and ease the suffering of millions of human and animal lives. However, their extensive and often uncontrolled use has led to the global spread of resistance in bacteria of medical and veterinary importance to an unprecedented level. This is threatening the ways we practice medicine and our ability to care for the sickest patients including those in need of life-saving treatments such as organ transplantation or cancer chemotherapy, and those in intensive care units. Antibiotic resistance is now recognised by the WHO as one of the greatest threats to human health and is increasingly topical within medical, veterinary and lay organisations of national and global reach.Enterococcus faecium, a bacterium carried harmlessly in the gut of humans and animals, has emerged as a leading cause of infections in critically ill and severely immunocompromised patients in hospitals. It has a propensity to accumulate and disseminate multiple antibiotic resistance determinants. Our previous work using a bacterial DNA fingerprinting technique called short-read whole-genome sequencing (WGS) established that E. faecium causing infections in hospital belongs to distinct strains from those found in livestock. In addition, we found different types of antibiotic resistance genes predominating in the two reservoirs. However, we also found instances of identical resistance genes, including to classes of antibiotics that are important in human medicine. Short-read WGS has limitations when trying to reconstruct the hierarchical levels of transmission units responsible for the spread of antibiotic resistance, which range from the whole bacterial strains, to consecutively smaller layers of mobile genetic elements known as plasmids and transposons down to the gene level. In order to decipher this "Russian doll" model, a different technique known as long-read WGS is required. Here, we propose to carefully select isolates for long-read WGS to allow us to quantify and understand the architectural context of shared antibiotic resistance genes between human and animal strains of E. faecium. Antibiotic susceptibility testing is a technique used daily in laboratories around the world to establish if antibiotics are still effective at treating bacterial strains of interest (i.e. ensuring the strains have not developed resistance). Resistance to antibiotics is mediated by genetic changes, hence whole genome sequencing has emerged as an attractive technology to characterise the full repertoire of known genetic changes that cause resistance and predict from the bacterial DNA if antibiotics are still effective. However, a complete understanding of the genetics governing resistance to antibiotics is required before WGS can be adopted to inform antibiotic prescribing. Our previous research has shown that WGS is very good at predicting the effectiveness of most antibiotics in E.faecium, except for 3 last-resort antibiotics used against the most resistant strains: daptomycin, tigecycline and linezolid. Here, we aim to redress this shortcoming by generating additional laboratory tests and sequencing data and to apply state-of-the art population genomic methods to improve predictions.

抗生素耐药性是一个健康连续体（人类，动物和环境）中最大的公共卫生威胁之一。抗生素对公共卫生具有非常重要的意义，在世界范围内每天都在使用，以拯救和减轻数百万人和动物的痛苦。然而，它们的广泛和经常不受控制的使用导致具有医学和兽医重要性的细菌的耐药性在全球范围内传播到前所未有的水平。这威胁到我们行医的方式和我们照顾病情最严重的病人的能力，包括那些需要挽救生命的治疗，如器官移植或癌症化疗，以及那些在重症监护室的病人。抗生素耐药性现已被世界卫生组织确认为人类健康的最大威胁之一，并日益成为国家和全球范围内的医学、兽医和非专业组织的热门话题。屎肠球菌是一种在人类和动物肠道中无害的细菌，已成为医院重症和严重免疫功能低下患者感染的主要原因。它有积累和传播多种抗生素耐药决定因素的倾向。我们以前的工作使用细菌DNA指纹技术称为短读全基因组测序（WGS）建立了E。引起医院感染的屎肠菌属于与家畜中发现的不同菌株。此外，我们发现不同类型的抗生素耐药基因占主导地位的两个水库。然而，我们也发现了相同的耐药基因，包括对人类医学重要的抗生素类。短读WGS在试图重建负责抗生素耐药性传播的传播单位的层次水平时存在局限性，其范围从整个细菌菌株到连续较小的移动的遗传元件层，称为质粒和转座子，一直到基因水平。为了破译这个“俄罗斯娃娃”模型，需要一种不同的技术，称为长读WGS。在这里，我们建议仔细选择分离株进行长读WGS，以使我们能够量化和理解人类和动物大肠杆菌菌株之间共享抗生素耐药基因的结构背景。屎室抗生素敏感性测试是世界各地实验室每天使用的一种技术，用于确定抗生素是否仍然有效治疗感兴趣的细菌菌株（即确保菌株没有产生耐药性）。对抗生素的耐药性是由遗传变化介导的，因此全基因组测序已经成为一种有吸引力的技术，可以检测导致耐药性的已知遗传变化的全部谱，并从细菌DNA中预测抗生素是否仍然有效。然而，在采用WGS为抗生素处方提供信息之前，需要完全了解控制抗生素耐药性的遗传学。我们之前的研究表明，WGS非常擅长预测大多数抗生素在屎肠球菌中的有效性，除了3种用于最耐药菌株的最后手段抗生素：达托霉素，替加环素和利奈唑胺。在这里，我们的目标是通过生成额外的实验室测试和测序数据来纠正这一缺点，并应用最先进的群体基因组方法来改善预测。