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

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.

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.