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世纪开发出来的，它彻底改变了现代医学。然而，由于过度使用这些化合物而产生的进化压力，已经在我们的环境中引起了普遍的抗菌素耐药性（AMR）基因，这对公众健康构成了重大威胁。不断引入亚抑制水平的AA进入我们的水系统被认为对AMR的发展有直接影响。由于抗菌素耐药性的复杂性，对其机制和影响因素的了解很少。抗菌药物的立体化学是影响其效力的一个基本性质，这一点在其环境发生和抗菌素耐药性方面还有待研究。本项目旨在了解抗菌药物在环境中的立体化学变化及其对微生物群落结构、组成和抗菌素耐药性进展的生物学效应。以下目标概述了该项目将如何面对这些目标：了解手性抗生素的环境转化机制。鉴定AA降解和AMR发生的耐药菌群。验证手性原子吸收剂的立体选择性与环境中细菌AMR菌株的丰度之间是否存在关联。这个跨学科项目结合了环境科学、微生物学和合成化学的专业知识。它将以纳米尺度（实验室）和宏观尺度（雅芳集水区，由威塞克斯水务公司确定）的废水和接收水中的原子吸收剂及其代谢物（氟喹诺酮类、β -内酰胺类和碳青霉烯类的1-3）为目标。将使用最先进的色谱和质谱分析方法（B. Kasprzyk-Hordern教授），通过PCR和基于16s rrna的宏基因组学（E. Fiel教授）鉴定负责立体选择性AA降解的耐药细菌分类群。非商用标准将在内部合成（S. Lewis博士）。增加我们对有害化学物质对环境和人类健康的影响的认识是非常重要的，而且这个项目有可能产生具有长期科学和社会影响的突破性研究。为了遏制抗生素耐药性的发展，必须实施更严格监管AA的政策。欧洲委员会最近在《水框架指令》下的观察清单中列入了一份抗生素的扩展清单（现在包括β -内酰胺和氟喹诺酮类药物）。UKWIR化学调查计划也将抗生素列为关键目标。威塞克斯水务公司（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，水务部门要深入了解aa对我们水循环的影响。该项目的目标非常适用于NERC的研究重点，包括：海洋环境或陆地和淡水环境中的生态毒理学、污染和水质；医疗卫生界面中的环境与健康微生物科学中的环境微生物学。此外，该项目与NERC的战略方向非常一致：从自然资源中受益，对环境危害的恢复力和管理环境变化。

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.