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

抗菌剂的立体化学对其环境归宿、生物效力和耐药性出现的影响

• 批准号: NE/N019261/1
• 负责人: Barbara Kasprzyk-Hordern
• 金额: $ 20.59万
• 依托单位: University of Bath
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=NE%2FN019261%2F1
• 关键词: Impact; stereochemistry; antimicrobial; agents; their

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.

本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。就环境中的医药产品而言，促进抗生素耐药细菌的风险是迄今为止最大的人类健康问题。持续向环境中引入亚抑制量的抗菌素（AAs）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，人们对其环境机制和影响因素知之甚少。有几个研究缺口需要解决，包括对受污染栖息地（例如废水）的研究，其中原子吸收剂、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存在。此外，AAs的立体化学（这是确定其生物效力的关键）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，因为在整个环境循环中，AAs的立体异构体轮廓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（并受到其影响）。这可能会进一步促进AMR的发展，这一现象在原子吸收剂的立体化学背景下从未被研究过。本项目假设原子吸收剂的立体化学性质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认为是两种不同的物质，它们可以引起不同的反应，从而导致药物的环境命运和效果的变化。该项目将：1；验证手性抗菌药物及其代谢物在废水处理和接收水中（立体选择性）转化的机制2。鉴定抗微生物药物（立体选择性）降解的耐药细菌分类群，并在立体异构体水平上研究抗微生物药物耐药性的发展3。通过纳入AAs（及其立体化学）和ARGs作为AMR指标，建议改变ERA。AAs的立体化学是复杂的，因为许多半合成剂作为非对映体的混合物销售，一些合成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，但我们也会考虑其他合成喹诺酮类药物，β -内酰胺类药物（如阿莫西林）和碳青霉烯类药物（如美罗培南）。考虑到更好地了解aa等手性污染物对环境和人类健康的影响的重要性，以及开发应对抗菌素耐药性的新解决方案的必要性，该项目有可能导致具有长期科学、技术和社会影响的突破性研究。

项目成果

Mass spectrometric strategies for the investigation of biomarkers of illicit drug use in wastewater.

• DOI: 10.1002/mas.21525
• 发表时间: 2018-05
• 期刊: Mass spectrometry reviews
• 影响因子: 6.6
• 作者: Hernández F;Castiglioni S;Covaci A;de Voogt P;Emke E;Kasprzyk-Hordern B;Ort C;Reid M;Sancho JV;Thomas KV;van Nuijs ALN;Zuccato E;Bijlsma L
• 通讯作者: Bijlsma L

Stereoselective metabolism of chloramphenicol by bacteria isolated from wastewater, and the importance of stereochemistry in environmental risk assessments for antibiotics.

从废水中分离的细菌对氯霉素的立体选择性代谢，以及立体化学在抗生素环境风险评估中的重要性。

• DOI: 10.1016/j.watres.2022.118415
• 发表时间: 2022
• 期刊: Water research
• 影响因子: 12.8
• 作者: Elder FCT

Stereoselective Bacterial Metabolism of Antibiotics in Environmental Bacteria - A Novel Biochemical Workflow.

• DOI: 10.3389/fmicb.2021.562157
• 发表时间: 2021
• 期刊: Frontiers in microbiology
• 影响因子: 5.2
• 作者: Elder FCT;Feil EJ;Pascoe B;Sheppard SK;Snape J;Gaze WH;Kasprzyk-Hordern B
• 通讯作者: Kasprzyk-Hordern B