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

Lead Research Organisation: University of Bath
Department Name: Chemistry

Abstract

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 waters
2. Identify resistant bacterial taxa responsible for (stereoselective) degradation of antimicrobial agents and to study the development of antimicrobial resistance at stereoisomeric level
3. 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.

Planned Impact

This project will provide cutting-edge advances in the understanding of the transformation mechanisms of antimicrobial agents and their biological effects including AMR. It will identify future research objectives directed at informed decision making on the wastewater treatment technologies used, the procedures applied in risk assessment of antimicrobial agents, the use of antimicrobial agents, relevant policies/regulations and consumer behaviours.

This project partners with a major UK water utility - Wessex Water, which will provide the opportunity for the project outcomes to be translated into effective applications within the water industry such as revision and implementation of existing and novel strategies aiming at reduction of impacts from antibiotics and AMR. In the light of the research, there may be grounds for legislative, procedural or policy changes in the area of wastewater treatment which are likely to be of significant interest to regulators. Collaboration with Environment Agency will allow for the development of a strategy aiming at limiting impacts from antibiotics and AMR.

Impact activities will include:
1. Development of inter-disciplinary and cross-sectoral research capability in AMR at the University of Bath.
2. Enhancing public-private sector collaborations: this project builds upon existing collaborations between public organisations and the private sector and will enhance these collaborations through the active involvement of the private sector in research activities. A workshop will be organised to facilitate knowledge exchange in particular in areas of pharmaceutical research, environmental management and water engineering.
3. Strengthening interdisciplinary and cross-sectoral collaborations in research: Due to its interdisciplinary nature, this project requires cross-sectoral collaborations in research both in formulating project objectives and in implementing research outcomes with an aim of measurable short and long-term impact in several AMR related areas including: water engineering, regulatory, pharmaceutical and health related sectors. This will be achieved via inclusion of key stakeholders as Project Partners representing water (Wessex Water) and regulatory (Environment Agency) sectors.
4. Communication of research outputs via publications in high IF journals, presentations at scientific conferences, popular media, articles in newspapers, webpages, presentations to the general public (e.g. Bath Science Café or Pint of Science talks), workshops and collaborative visits (to facilitate knowledge exchange between academic and public/private sector) and other outreach activities (e.g. promotion of research at schools).
5. Acquisition of key skills by the project researchers through a unique training programme that involves engagement with integrated disciplines conducting cutting edge research and exposure to private sector.

Publications

10 25 50
 
Description Collaboration with Astra Zeneca 
Organisation AstraZeneca
Country United Kingdom 
Sector Private 
PI Contribution PhD studentship: expertise, facilities, co-funded by EPSRC
Collaborator Contribution PhD studentship: expertise, financial contribution
Impact Excellent proof-of concept results, presentations.
Start Year 2016
 
Description Collaboration with Environment Agency 
Organisation Environment Agency
Country United Kingdom 
Sector Public 
PI Contribution Collaboration within NE/N019261/1 project entitled: 'Impact of stereochemistry of antimicrobial agents on their environmental fate, biological potency and the emergence of resistance'
Collaborator Contribution Collaboration within NE/N019261/1 project entitled: 'Impact of stereochemistry of antimicrobial agents on their environmental fate, biological potency and the emergence of resistance'
Impact Ongoing
Start Year 2016
 
Description Collaboration with Wessex Water 
Organisation Wessex Water
Country United Kingdom 
Sector Private 
PI Contribution expertise, equipment, facilities
Collaborator Contribution expertise, equipment, facilities
Impact Several, including academic papers: Petrie, B., Proctor, K., Youdan, J., Barden, R. and Kasprzyk-hordern, B., 2017. Critical evaluation of monitoring strategy for the multi-residue determination of 90 chiral and achiral micropollutants in effluent wastewater. Science of the Total Environment, 579, pp. 569-578. Petrie, B., Gravell, A., Mills, G. A., Youdan, J., Barden, R. and Kasprzyk-Hordern, B., 2016. In situ calibration of a new chemcatcher configuration for the determination of polar organic micropollutants in wastewater effluent. Environmental Science & Technology, 50 (17), pp. 9469-9478. Petrie, B., Youdan, J., Barden, R. and Kasprzyk-Hordern, B., 2016. A new framework to diagnose the direct disposal of prescribed drugs in wastewater - a case study of the antidepressant fluoxetine. Environmental Science & Technology, 50 (7), pp. 3781-3789. Petrie, B., Youdan, J., Barden, R. and Kasprzyk-Hordern, B., 2016. Multi-residue analysis of 90 emerging contaminants in liquid and solid environmental matrices by ultra-high-performance liquid chromatography tandem mass spectrometry. Journal of Chromatography A, 1431, pp. 64-78. Petrie, B., Barden, R. and Kasprzyk-Hordern, B., 2015. A review on emerging contaminants in wastewaters and the environment:current knowledge, understudied areas and recommendations for future monitoring. Water Research, 72, pp. 3-27.
Start Year 2012
 
Description What's Your water telling you? Urban water profiling inform the state of the environment and public health 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Public talk delivered by Kasprzyk-Hordern B entitled: 'What's Your water telling you? Urban water profiling inform the state of the environment and public health', RSC Event, Bristol, 13th Feb 2018, University of the West of England
Year(s) Of Engagement Activity 2017
 
Description 3. Cartwright, N and Kasprzyk-Hordern, B. To understand the risks to the environment from chemicals, , Environment Agency meeting 'Working Together for a Better Environment', Bristol, 21st February 2017 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Industry/Business
Results and Impact Talk on collaboration between University of Bath, Wessex Water and Environment Agency
Year(s) Of Engagement Activity 2017
URL https://www.instituteofwater.org.uk/events-info/613/
 
Description Innovation through partnership working, DEFRA, London 15th November 2016. 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact Talk at DEFRA WQ Team away day
Year(s) Of Engagement Activity 2016
 
Description Public talk entitled: 'Healthy waters: Pharmaceuticals in the environment - cause for concern? Bath Festival of Nature, 2nd June 2017 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Public talk delivered by Kasprzyk-Hordern. Title: Healthy waters: Pharmaceuticals in the environment - cause for concern? Bath Festival of Nature, 2nd June 2017.
Year(s) Of Engagement Activity 2017
 
Description Talk by B. Kasprzyk-Hordern, My career in water, 18th UK Young Water, Professionals Conference, University of Bath, 10 -12th April 2017 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Industry/Business
Results and Impact Talk by B. Kasprzyk-Hordern, My career in water, 18th UK Young Water, Professionals Conference, University of Bath, 10 -12th April 2017
Year(s) Of Engagement Activity 2017
 
Description Talk by Kasprzyk-Hordern, Pharmaceuticals in the environment - cause for concern?, Viewpoints Keynsham: Healthy Water, 23rd of March 2017 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Public talk by Kasprzyk-Hordern, Pharmaceuticals in the environment - cause for concern?, Viewpoints Keynsham: Healthy Water, 23rd of March 2017
Year(s) Of Engagement Activity 2017
 
Description Talk delivered by Kasprzyk-Hordern, entitled: Water fingerprinting for public health assessment', Wetenschappelijke Advies Raad / Scientific Advisory Council KWR, Nieuwegein, the Netherlands, 1st of June 2017 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Industry/Business
Results and Impact Talk delivered by Kasprzyk-Hordern, entitled: Water fingerprinting for public health assessment' at Wetenschappelijke Advies Raad / Scientific Advisory Council KWR, Nieuwegein, the Netherlands, 1st of June 2017
Year(s) Of Engagement Activity 2017
 
Description WBE for drug use and public health assessment' Amsterdam International Water Week Conference, 30 October - 3 November 2017, Amsterdam 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Industry/Business
Results and Impact Talk delivered by Kasprzyk-Hordern entitled: 'WBE for drug use and public health assessment' at Amsterdam International Water Week Conference
Year(s) Of Engagement Activity 2017