Predictive modelling of a novel anti-adhesion therapy to combat bacterial colonisation of burn wounds

As the development of new classes of antibiotics slows, bacterial resistance to existing antibiotics is becoming an increasing problem. A potential solution is to develop treatment strategies with an alternative mode of action. We consider one such strategy: anti-adhesion therapy. Whereas antibiotics act directly upon bacteria, either killing them or inhibiting their growth, anti-adhesion therapy impedes the binding of bacteria to host cells. This prevents bacteria from deploying their arsenal of virulence mechanisms, while simultaneously rendering them more susceptible to natural and artificial clearance. In this paper, we consider a particular form of anti-adhesion therapy, involving biomimetic multivalent adhesion molecule 7 coupled polystyrene microbeads, which competitively inhibit the binding of bacteria to host cells. We develop a mathematical model, formulated as a system of ordinary differential equations, to describe inhibitor treatment of a Pseudomonas aeruginosa burn wound infection in the rat. Benchmarking our model against in vivo data from an ongoing experimental programme, we use the model to explain bacteria population dynamics and to predict the efficacy of a range of treatment strategies, with the aim of improving treatment outcome. The model consists of two physical compartments: the host cells and the exudate. It is found that, when effective in reducing the bacterial burden, inhibitor treatment operates both by preventing bacteria from binding to the host cells and by reducing the flux of daughter cells from the host cells into the exudate. Our model predicts that inhibitor treatment cannot eliminate the bacterial burden when used in isolation; however, when combined with regular or continuous debridement of the exudate, elimination is theoretically possible. Lastly, we present ways to improve therapeutic efficacy, as predicted by our mathematical model.Author summary: Humankind is engaged in an arms race; one we are in danger of losing. Since the development and application of the first antibiotics, resistant strains of bacteria have steadily emerged. As the rate of discovery of new antibiotics slows, the threat increases. At present, 700,000 individuals globally die each year due to antimicrobial resistance and this number is predicted to rise to 10 million per year by 2050 unless fresh action is taken. It is important, therefore, that we explore alternative treatment strategies to replace or complement traditional antimicrobials. Here we use mathematical models to explain and predict the effects of a novel anti-adhesion therapy applied to infected burn wounds. This theoretically resistance-proof therapy operates by impeding bacteria from binding to host cells by blocking the host cell binding sites. This prevents bacteria from accessing nutrients and renders them susceptible to artificial clearance. Fitting our model to experimental data, we identify a number of valid parameter sets, and predict the conditions under which treatment will be effective for each set. These predictions are experimentally testable, and could be used to guide the development and application of anti-adhesion treatments in a clinical setting.