Stereochemistry of antimicrobial agents in the urban water cycle and its impact upon the evolution of antimicrobial resistance

抗菌剂(AA)是在20世纪发展起来的，它彻底改变了现代医学。然而，过度使用这些化合物带来的进化压力导致了环境中普遍存在的抗菌素耐药(AMR)基因，这对公众健康构成了重大威胁。在我们的水系统中不断引入亚抑制水平的AA被认为对AMR的发展有直接影响。由于AMR的复杂性，目前对其发病机制及影响因素知之甚少。抗菌剂的立体化学是影响其效力的基本性质，关于它们在环境中的存在和AMR，这一点还有待研究。该项目旨在了解抗菌剂的立体化学是如何在环境中转化的，以及它们对微生物群落结构、组成和AMR进展的生物学影响。以下目标概述了该项目将如何面对这些目标：1.了解手性抗生素的环境转化机制。鉴定导致AA降解和AMR发生的耐药细菌类群。为了验证手性氨基酸的立体选择性与环境中AMR菌株的丰富程度之间是否存在关联。这个跨学科的项目结合了环境科学、微生物学和合成化学的专业知识。它将针对废水和接收水中的AAs及其代谢物(1-3种氟喹诺酮类药物、β-内酰胺类和碳青霉烯类)，在纳米尺度(基于实验室)和宏观尺度(雅芳集水点，由Wessex Water确定)。将使用最先进的层析和质谱分析方法(B.Kasprzyk-Hordern教授)，通过聚合酶链式反应和基于16S rRNA的元基因组学(E.Fiel教授)鉴定负责立体选择性降解AA的耐药细菌分类群。非商用标准将在内部合成(S·刘易斯博士)增加我们对AA对环境和人类健康的影响的认识是非常重要的，这个项目有可能产生具有长期科学和社会影响的开创性研究。为了遏制AMR的进展，必须实施涉及更严格的AA监管的政策。欧盟委员会最近根据《水框架指令》将抗生素的扩展清单列入观察名单(现在包括β-内酰胺和氟喹诺酮的例子)。UKWIR化学调查方案也将抗生素列为主要目标。Wessex Water(WW)致力于提供高质量的水和环境服务，以保护健康和改善环境，并将与AA相关的风险视为关键优先事项。至关重要的是，水务部门必须深入了解环境影响评估对我们水循环的影响。该项目的目的非常适用于国家环境研究中心的研究重点，包括以下领域：海洋环境或陆地和淡水环境中的生态毒理学、污染和水质；医疗与健康界面中的环境与健康；以及微生物科学中的环境微生物学。此外，该项目与国家环境研究中心的战略方向相一致：受益于自然资源，对环境危害的应变能力和管理环境变化。

Antimicrobial agents (AA) were developed in the 20th century and revolutionised modern medicine. The subsequent evolutionary pressure exerted by overuse of these compounds, however, has given rise to prevalent antimicrobial resistance (AMR) genes in our environment, which pose a major threat to public health. Constant introduction of sub-inhibitory levels of AA into our water system is believed to have a direct influence on the development of AMR. Due to the complexity of AMR, there is scarce knowledge of the mechanisms and influencing factors involved in this. The stereochemistry of antimicrobial agents is a fundamental property affecting their potency, and this has yet to be studied with regards to their environmental occurrence and AMR. This project will aim to understand how the stereochemistry of antimicrobial agents is transformed in the environment and the biological effects they have on microbial community structure, composition, and AMR advancement. The following objectives outline how this project will confront these aims:1. To understand the environmental transformation mechanisms of chiral antibiotics.2. To identify resistant bacterial taxa responsible for AA degradation and AMR development.3. To verify if there is an association between the stereoselectivity of chiral AAs, and the abundance of AMR strains of bacteria in the environment.This interdisciplinary project combines expertise from environmental science, microbiology and synthetic chemistry. It will target AAs and their metabolites (1-3 of fluoroquinolones, beta-lactams and carbapenems) in wastewater and receiving waters, at nanocosm (lab-based) and macrocosm (Avon Catchment sites, identified by Wessex Water) scale. State-of-the-art chromatography and mass spectrometry analytical methods (Prof. B. Kasprzyk-Hordern) will be used, with resistant bacterial taxa responsible for stereoselective AA degradation identified via PCR and 16s rRNA-based metagenomics (Prof. E. Fiel). Non-commercially available standards will be synthesised in-house (Dr. S. Lewis). It is of great importance to increase our knowledge of the impact AAs impose upon the environment and human health, and this project has the potential to produce ground-breaking research with long term scientific and societal impact.To curtail the advancement of AMR, policies involving stricter regulation of AA must be implemented. The European Commission has recently included an extended list of antibiotics on the Watch List under the Water Framework Directive (now including beta-lactam and fluoroquinolone examples). The UKWIR Chemical Investigations Programme also outline antibiotics as a key target. Wessex Water (WW) is committed to providing high quality water and environmental services that protect health and improve the environment and consider the risks associated with AAs as a key priority. It is crucially important that the water sector gains a deep understanding of the impact AAs have on our water cycle. The aim of this project is strongly applicable to the NERC's research priorities, which include areas such as: Ecotoxicology, Pollution & Water Quality within Marine Environments or Terrestrial & Freshwater Envrironments; Environment and Health within Medical & Health Interface; and Environmental Microbiology within Microbial Sciences. In addition, this project is well aligned with the NERC's strategic directions of: Benefiting from Natural Resources, Resilience to Environmental Hazards & Managing Environmental Change.