Using stochastic cellular automata to model and define sufficient conditions for the survival of Enterococcus faecalis biofilms with the pCF10 plasmid under erythromycin treatment

A biofilm is a community of microorganisms adhered to a surface, bound together by extracellular polymeric substances (EPS). They are ubiquitous in nature and develop on a range of surfaces including living tissue. Biofilms themselves typically do not negatively affect their host, but under certain conditions they can retain pathogenic features and cause a wide range of illnesses including persistent or chronic infections. In this study, we look at the bacterium Enterococcus faecalis. E. faecalis is a gram-positive, commensal bacterium commonly found in the human gastrointestinal tract. Generally, commensal E. faecalis does not negatively impact human health, but pathogenic strains have been found to acquire mobile genetic elements, including plasmids. When E. faecalis with the pCF10 plasmid forms a biofilm it constructs raised complex structures with variable cellular packing, including aggregates, instead of a homogeneous and less densely packed biofilm above a rigid base. This reconfiguration of the biofilm confers resistance to high levels of erythromycin. For this study, we carried out biological experiments which show that pCF10-containing E. faecalis biofilms undergo a rapid reconfiguration of its initial architecture, resulting in a doubling of cellular population over a single hour of antibiotic treatment. We developed a mathematical and computational model, calibrated using image processing techniques, to identify the characteristics of the biofilm's spatial architecture that allow for the rapid one-hour reconfiguration under treatment. This model involves both stochastic cellular automata and deterministic partial differential equations. The numerical simulations carried out in this study demonstrate that biofilm survival requires both the robust formation of initial complex structures and an associated extracellular DNA (eDNA) cloud. These findings highlight the fundamental role of biofilm heterogeneity, containing aggregated structures with an associated eDNA cloud, in erythromycin resistance of E. faecalis with the pCF10 plasmid. The identification of eDNA as a target to increase the susceptibility of the biofilm to erythromycin could ultimately improve antibiotic treatment protocols.