TY - JOUR
T1 - Predictive modelling of a novel anti-adhesion therapy to combat bacterial colonisation of burn wounds
AU - Roberts, Paul A.
AU - Huebinger, Ryan M.
AU - Keen, Emma
AU - Krachler, Anne Marie
AU - Jabbari, Sara
N1 - Funding Information:
PAR, EK, AMK and SJ gratefully acknowledge support from the Biotechnology and Biological Sciences Research Council (grant code: BB/M021386/1, http://www.bbsrc.ac.uk/). PAR and SJ would also like to thank the Wellcome Trust (grant code: 1516ISSFFEL9, www.wellcome.ac.uk/) for funding a parameterisation workshop at the University of Birmingham (UK). RMH acknowledges support from the Golden Charity Guild Charles R. Baxter, MD Chair in Burn Surgery (www.utsouthwestern.edu) which provided research funding. AMK thanks the UT System for support through a University of Texas System Science and Technology Acquisition and Retention (STARs) Program award (https://www.utsystem.edu/offices/health-affairs/stars-program). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Publisher Copyright:
© 2018 Roberts et al. http://creativecommons.org/licenses/by/4.0/
PY - 2018/5
Y1 - 2018/5
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85048150335&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85048150335&partnerID=8YFLogxK
U2 - 10.1371/journal.pcbi.1006071
DO - 10.1371/journal.pcbi.1006071
M3 - Article
C2 - 29723210
AN - SCOPUS:85048150335
VL - 14
JO - PLoS Computational Biology
JF - PLoS Computational Biology
SN - 1553-734X
IS - 5
M1 - e1006071
ER -