Developing experimental and theoretical models to study antimicrobial resistance and resilience in polymicrobial biofilms

Pathogenic microbial biofilms are responsible for >80% of all human infections (CDC) and frequently consist of multiple microbial species. Importantly, these multi-species “polymicrobial” biofilms (PMBs) are highly refractory to antimicrobials and difficult to treat. It is therefore crucial to understand the dynamics of PMBs and their role in the evolution of antimicrobial resistance (AMR). However, these PMB structures are highly complex and frequently consist of poorly defined strain variants, which makes them inherently difficult to study. Therefore, we need a much more controlled, bottom-up approach where the PMB is constructed and manipulated under well-defined conditions, in order to gain deeper insights into the fundamental parameters that underpin the antimicrobial resistance and resilience of PMBs.

Out project will address the need for a well-defined framework to study PMBs both experimentally and theoretically. This will be a collaborative and multi-disciplinary effort across Bath, Bristol and Exeter and it leverages the broad expertise of the team across clinical microbiology, microfluidics, imaging and mathematical modelling.

We will rationally design PMBs from the bottom up. Using defined microbial species, we will construct PMBs in highly controlled experimental environments. This will involve the use of new microfluidics/microscopy methodologies to study biofilm dynamics and antibiotic resistance evolution in real time. These will be complemented by laboratory biofilm assays facilitating higher throughput and downstream -omics analysis in the future. In parallel, we will build capacity to simulate PMBs. This skill, to be developed across the team, will guide experiments and generate predictions in the future. Our framework will be widely applicable to a range of microbial species, including bacteria and fungi, and enable us to reconstitute and investigate medically relevant PMBs.

Overall, the work will establish a versatile framework to investigate antimicrobial efficacy and antimicrobial resistance evolution in diverse PMBs. Additionally, the project will facilitate sharing of experimental and theoretical expertise across the GW4 network and lay the foundation for larger funding applications in the future.