Stereochemistry of antimicrobial agents in the urban water cycle and its impact upon the evolution of antimicrobial resistance

Antimicrobial agents (AA) were developed in the 20th century and revolutionised modern medicine. The subsequent evolutionary pressure exerted by overuse of these compounds, however, has given rise to prevalent antimicrobial resistance (AMR) genes in our environment, which pose a major threat to public health. Constant introduction of sub-inhibitory levels of AA into our water system is believed to have a direct influence on the development of AMR. Due to the complexity of AMR, there is scarce knowledge of the mechanisms and influencing factors involved in this. The stereochemistry of antimicrobial agents is a fundamental property affecting their potency, and this has yet to be studied with regards to their environmental occurrence and AMR.

This project will aim to understand how the stereochemistry of antimicrobial agents is transformed in the environment and the biological effects they have on microbial community structure, composition, and AMR advancement.

The following objectives outline how this project will confront these aims:
1. To understand the environmental transformation mechanisms of chiral antibiotics.
2. To identify resistant bacterial taxa responsible for AA degradation and AMR development.
3. To verify if there is an association between the stereoselectivity of chiral AAs, and the abundance of AMR strains of bacteria in the environment.

This interdisciplinary project combines expertise from environmental science, microbiology and synthetic chemistry. It will target AAs and their metabolites (1-3 of fluoroquinolones, beta-lactams and carbapenems) in wastewater and receiving waters, at nanocosm (lab-based) and macrocosm (Avon Catchment sites, identified by Wessex Water) scale. State-of-the-art chromatography and mass spectrometry analytical methods (Prof. B. Kasprzyk-Hordern) will be used, with resistant bacterial taxa responsible for stereoselective AA degradation identified via PCR and 16s rRNA-based metagenomics (Prof. E. Fiel). Non-commercially available standards will be synthesised in-house (Dr. S. Lewis).

It is of great importance to increase our knowledge of the impact AAs impose upon the environment and human health, and this project has the potential to produce ground-breaking research with long term scientific and societal impact.
To curtail the advancement of AMR, policies involving stricter regulation of AA must be implemented. The European Commission has recently included an extended list of antibiotics on the Watch List under the Water Framework Directive (now including beta-lactam and fluoroquinolone examples). The UKWIR Chemical Investigations Programme also outline antibiotics as a key target. Wessex Water (WW) is committed to providing high quality water and environmental services that protect health and improve the environment and consider the risks associated with AAs as a key priority. It is crucially important that the water sector gains a deep understanding of the impact AAs have on our water cycle.

The aim of this project is strongly applicable to the NERC's research priorities, which include areas such as: Ecotoxicology, Pollution & Water Quality within Marine Environments or Terrestrial & Freshwater Envrironments; Environment and Health within Medical & Health Interface; and Environmental Microbiology within Microbial Sciences. In addition, this project is well aligned with the NERC's strategic directions of: Benefiting from Natural Resources, Resilience to Environmental Hazards & Managing Environmental Change.