Machineni, Lakshmi and Pawar, Parag D
(2016)
A Three-dimensional Computational Model to Investigate the Influence of Spatial Heterogeneity on the Antibiotic Tolerance of Bacterial Biofilms.
Biomath Communications, 3.
ISSN 2367-5241
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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. In the first phase that lasted ≈4h, the total biomass reduced
dramatically (≈ 40% reduction). In this phase, the biofilm was dominated
by subpopulations of slow-growing cells. There was a strong correlation
between dead cells and fast-growing populations. The fraction of inactive
cells increased with time, reaching a peak after 4h of treatment. The second
phase lasted for ≈8h, and was characterized by a decrease in the number
of slow-growing cells, owing to increased nutrient availability. Complete
eradication of the biofilm was observed in the third phase of treatment.
Interestingly, we observed a threshold for the antibiotic concentration below which the treated biofilm exhibited increased lifetimes compared to the
untreated one. Quorum-sensing (QS) biofilms were more tolerant, because
of the production of EPS. This was further validated by the observation
that the average diffusion distances were much higher for the QS-positive
biofilm. Taken together, our results indicate that spatial heterogeneity of
bacterial cells and EPS contribute to the antibiotic tolerance of biofilms in
the absence of genetic triggers. A systematic investigation of the structural
properties of these microniches of the biofilm, and their response to treatment may shed light on the biophysical mechanisms of antibiotic resistance
of bacterial biofilms.
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