A Three-dimensional Computational Model to Investigate the Influence of Spatial Heterogeneity on the Antibiotic Tolerance of Bacterial Biofilms

Abstract

In this work, we investigate the antibiotic susceptibility of bacterial biofilms with the exclusion of genetic factors using a 3D cellular automata model for biofilm growth. Each cell is treated as an individual entity, and is tracked separately as the simulation marches forward in time. The model incorporates processes of nutrient and antibiotic transport, cell growth, division, death, and detachment. In addition, the dynamics and spatial distributions of slow- and fast-growing cells were also monitored to the level of individual cells, and cell clusters. The model predicted the formation of a mosaic-like architecture comprising of metabolically dormant cellular microniches embedded within faster growing cell clusters and EPS. These inactive cells were less susceptible to killing by antibiotic. We propose that (i) the surrounding high-activity cell clusters act as a reaction-diffusion barrier, thereby restricting antibiotic penetration to the low growth-rate clusters, and (ii) low-activity cells consume antibiotics at a diminished rate, thereby reduced efficacy of treatment. The antibiotic response exhibited three distinct phases. ...