Modelling mechanical and chemical treatment of biofilms with two phenotypic resistance mechanisms

Bacterial biofilms are notoriously difficult to eradicate owing to a number of tolerance mechanisms including physiological, physical, genotypic and phenotypic variations. Recent focus has shifted to phenotypic tolerance which is apparently the main defence mechanism that protects biofilms against long-term disinfection. Previous mathematical models have addressed phenotypic dynamics by considering adaptive response and persister formation separately. The aim of this manuscript is to consider a combined model to understand the interplay between these two defence mechanisms. We find that each mechanism protects the biofilm differently and hence responds differently to antibiotic challenge. We focus on on-off dosing that has been shown to eradicate each subpopulation alone. Our results indicate that the combined resistance exhibits qualitatively similar behavior to persister formation for short dosing times, and similar behavior to adaptive resistance for long dosing times. To further contrast the behavior of the model under different parameter regimes, we explore two classes of combination treatment that include mechanical and chemical treatments. The examples focus on different applications - pipe clearance and dental carrie prevention - and demonstrate the underlying conclusion that adaptive and persister mechanism provide protection for different challenges and are thus not redundant systems and each may require specific treatment plans.