Impact of stereochemistry of antimicrobial agents on their environmental fate, biological potency and the emergence of resistance

该项目旨在了解和解决抗菌药物在其环境循环中的立体异构对抗菌药物耐药性发展背后机制的影响。抗生素耐药性细菌的推广风险是迄今为止环境中药品最大的人类健康问题。持续向环境中引入亚抑菌量的抗菌剂（AAs）被认为与抗菌药物耐药性（AMR）直接相关。不幸的是，由于AMR问题的多维性，对环境中的机制和影响因素知之甚少。有几个研究空白需要解决，包括研究受污染的栖息地（如废水），其中AA，共选择剂，携带抗性决定因素的细菌和细菌生长的有利条件同时盛行。此外，AA的立体化学（这是定义其生物学效力的关键）从未在其环境命运和影响的背景下进行过研究。这是一个疏忽，因为在整个环境周期中，AA的立体异构体特征的变化将导致环境中存在的微生物群落的组成和结构的变化（并受其影响）。这可能会进一步促进AMR的发展，这是一种从未在AA立体化学背景下研究过的现象。该项目假定，AA的立体化学决定了它们的环境命运和生物效应。它还假设，同一AA的两种对映体应被视为两种不同的物质，可以引起不同的反应，导致环境命运和药物效应的变化。该项目将：1。验证废水处理过程中和接收水中手性抗菌剂及其代谢物的（立体选择性）转化机制2。鉴定负责抗菌剂（立体选择性）降解的耐药细菌分类群，并在立体异构水平上研究抗菌剂耐药性的发展3。建议通过纳入AA（及其立体化学）和ARG作为AMR指示剂对ERA进行变更AA的立体化学很复杂，因为许多半合成药剂作为非对映异构体的混合物销售，并且许多合成药剂作为外消旋体使用。在这个项目中，我们将重点关注氧氟沙星和氯霉素，但我们也将考虑其他合成喹诺酮类，β-内酰胺类（如阿莫西林）和碳青霉烯类（例如美罗培南）。考虑到更好地了解诸如AA等手性污染物对环境和人类健康的影响的重要性，以及需要制定新的解决办法来应对抗生素耐药性，该项目有可能导致具有长期科学，技术和社会影响的开创性研究。

This project aims to understand and address the impact of stereoisomerism of antimicrobial agents in their environmental cycle on mechanisms behind the development of antimicrobial resistance. The risk of promotion of antibiotic resistant bacteria is by far the greatest human health concern with regards to medicinal products in the environment. The continuous introduction of sub-inhibitory quantities of antimicrobial agents (AAs) to the environment is believed to be directly linked with antimicrobial resistance (AMR). Unfortunately, there is little knowledge of mechanisms in the environment and influencing factors due to the multi-dimensional nature of the AMR problem. There are several research gaps that need to be addressed including research into contaminated habitats (e.g. wastewater) where AAs, co-selecting agents, bacteria carrying resistance determinants and favourable conditions for bacterial growth prevail at the same time. Furthermore, the stereochemistry of AAs (which is key in defining their biological potency) has never been studied in the context of their environmental fate and effects. This is an oversight as changes in stereoisomeric profile of AAs throughout their environmental cycle will lead to (and be influenced by) changes in the composition and structure of microbial communities present in the environment. This might further contribute to the development of AMR, a phenomenon that has never been the subject of investigation in the context of stereochemistry of AAs. This project postulates that stereochemistry of AAs determines their environmental fate and biological effects. It also hypothesizes that two enantiomers of the same AA should be recognised as two different substances that can elicit different responses leading to changes in the environmental fate and effects of the drug. The project will: 1. Verify the mechanisms of (stereoselective) transformation of chiral antimicrobial agents and their metabolites during wastewater treatment and in receiving waters2. Identify resistant bacterial taxa responsible for (stereoselective) degradation of antimicrobial agents and to study the development of antimicrobial resistance at stereoisomeric level3. Recommend changes to ERA via inclusion of AAs (and their stereochemistry) and ARGs as AMR indicators The stereochemistry of AAs is complex, as many of the semi-synthetic agents are marketed as mixtures of diastereomers and a number of synthetic agents are used as racemates. In this project we will focus on ofloxacin and chloramphenicol, but we will also consider other synthetic quinolones, Beta-lactams (e.g. amoxicillin) and carbapenems (e.g. meropenem).Considering the importance of better understanding environmental and human health impacts from chiral pollutants such as AAs and the need for the development of new solutions tackling AMR, this project has the potential to lead to groundbreaking research with long term scientific, technological and societal impact.