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剂在其环境周期中的立体异构体对抗菌素耐药性发展背后的机制的影响。到目前为止，与环境中的医药产品有关的人类健康最大的担忧是推广抗生素耐药细菌的风险。持续向环境中引入亚抑制量的抗菌剂被认为与抗菌素耐药性(AMR)直接相关。不幸的是，由于AMR问题的多维性，人们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弥补，包括对受污染的生境(例如废水)的研究，在这些研究中，AAs、共选择剂、携带抗药性决定因素的细菌和细菌生长的有利条件同时盛行。此外，AAs的立体化学(这是确定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研究。这是一个疏忽，因为在其整个环境周期中，AAs立体异构体概况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)。这可能进一步促进AMR的发展，这一现象从来不是在AAs立体化学背景下研究的主题。该项目假设AAs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的两个对映体应该被识别为两种不同的物质，可以引起不同的反应，从而改变药物的环境命运和影响。该项目将：1.验证手性抗菌剂及其代谢物在废水处理和接受水过程中(立体选择性)转化的机理2。鉴定负责(立体选择性)降解抗菌剂的耐药细菌分类群，并研究立体异构体水平3的抗菌素耐药性的发展。建议通过将AAs(及其立体化学)和ARGs作为AMR指标来改变ERA。AAs的立体化学是复杂的，因为许多半合成试剂以非对映异构体混合物的形式在市场上销售，一些合成试剂被用作外消旋。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的喹诺酮类药物、β-内酰胺类(如阿莫西林)和碳青霉烯类(如美罗培南)。考虑到更好地了解AAs等手性污染物对环境和人类健康的影响的重要性，以及开发应对AMR的新解决方案的必要性，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.