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Metabolic modeling of a chronic wound biofilm consortium predicts spatial partitioning of bacterial species

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ABSTRACT

Background: Chronic wounds are often colonized by consortia comprised of different bacterial species growing as biofilms on a complex mixture of wound exudate. Bacteria growing in biofilms exhibit phenotypes distinct from planktonic growth, often rendering the application of antibacterial compounds ineffective. Computational modeling represents a complementary tool to experimentation for generating fundamental knowledge and developing more effective treatment strategies for chronic wound biofilm consortia.

Results: We developed spatiotemporal models to investigate the multispecies metabolism of a biofilm consortium comprised of two common chronic wound isolates: the aerobe Pseudomonas aeruginosa and the facultative anaerobe Staphylococcus aureus. By combining genome-scale metabolic reconstructions with partial differential equations for metabolite diffusion, the models were able to provide both temporal and spatial predictions with genome-scale resolution. The models were used to analyze the metabolic differences between single species and two species biofilms and to demonstrate the tendency of the two bacteria to spatially partition in the multispecies biofilm as observed experimentally. Nutrient gradients imposed by supplying glucose at the bottom and oxygen at the top of the biofilm induced spatial partitioning of the two species, with S. aureus most concentrated in the anaerobic region and P. aeruginosa present only in the aerobic region. The two species system was predicted to support a maximum biofilm thickness much greater than P. aeruginosa alone but slightly less than S. aureus alone, suggesting an antagonistic metabolic effect of P. aeruginosa on S. aureus. When each species was allowed to enhance its growth through consumption of secreted metabolic byproducts assuming identical uptake kinetics, the competitiveness of P. aeruginosa was further reduced due primarily to the more efficient lactate metabolism of S. aureus. Lysis of S. aureus by a small molecule inhibitor secreted from P. aeruginosa and/or P. aeruginosa aerotaxis were predicted to substantially increase P. aeruginosa competitiveness in the aerobic region, consistent with in vitro experimental studies.

Conclusions: Our biofilm modeling approach allows the prediction of individual species metabolism and interspecies interactions in both time and space with genome-scale resolution. This study yielded new insights into the multispecies metabolism of a chronic wound biofilm, in particular metabolic factors that may lead to spatial partitioning of the two bacterial species. We believe that P. aeruginosa lysis of S. aureus combined with nutrient competition is a particularly relevant scenario for which model predictions could be tested experimentally.

Electronic supplementary material: The online version of this article (doi:10.1186/s12918-016-0334-8) contains supplementary material, which is available to authorized users.

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Spatially resolved predictions for single species biofilms. aP. aeruginosa with a maximum biofilm of thickness W = 30 μm. bS. aureus with a maximum biofilm of thickness W = 90 μm
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Fig2: Spatially resolved predictions for single species biofilms. aP. aeruginosa with a maximum biofilm of thickness W = 30 μm. bS. aureus with a maximum biofilm of thickness W = 90 μm

Mentions: Spatially resolved predictions obtained after 1000 h showed that the P. aeruginosa biofilm (Fig. 2a) were characterized by high biomass concentrations throughout the biofilm, low oxygen concentrations near the bottom of the biofilm furthest from the oxygen source, low glucose concentrations near the top of the biofilm furthest from the glucose source, and acetate and succinate as the primary metabolic byproducts. If the biofilm thickness was chosen larger than Wmax = 30 μm, the P. aeruginosa biomass concentration dropped below 10 g/L at the bottom of the biofilm due to the combination of low oxygen penetration and very small anaerobic growth rates (see glucose results in Table 4). The S. aureus biofilm model predicted much deeper oxygen penetration (~50 μm vs. ~25 μm) due to more efficient use of oxygen for glucose oxidation (Fig. 2b). Superior anaerobic growth allowed S. aureus to produce much thicker biofilms under the same environmental conditions. Otherwise, the predictions were similar to those obtained with P. aeruginosa with lactate replacing succinate as a primary byproduct. If the S. aureus biofilm thickness was chosen larger than Wmax = 90 μm, the biomass concentration dropped below 10 g/L near the top of the biofilm due to inadequate glucose penetration. The effect of the metabolite mass transfer coefficients on concentration gradients within the S. aureus biofilm are shown in Additional file 1: Figure S1.Fig. 2


Metabolic modeling of a chronic wound biofilm consortium predicts spatial partitioning of bacterial species
Spatially resolved predictions for single species biofilms. aP. aeruginosa with a maximum biofilm of thickness W = 30 μm. bS. aureus with a maximum biofilm of thickness W = 90 μm
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Related In: Results  -  Collection

License 1 - License 2
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getmorefigures.php?uid=PMC5015247&req=5

Fig2: Spatially resolved predictions for single species biofilms. aP. aeruginosa with a maximum biofilm of thickness W = 30 μm. bS. aureus with a maximum biofilm of thickness W = 90 μm
Mentions: Spatially resolved predictions obtained after 1000 h showed that the P. aeruginosa biofilm (Fig. 2a) were characterized by high biomass concentrations throughout the biofilm, low oxygen concentrations near the bottom of the biofilm furthest from the oxygen source, low glucose concentrations near the top of the biofilm furthest from the glucose source, and acetate and succinate as the primary metabolic byproducts. If the biofilm thickness was chosen larger than Wmax = 30 μm, the P. aeruginosa biomass concentration dropped below 10 g/L at the bottom of the biofilm due to the combination of low oxygen penetration and very small anaerobic growth rates (see glucose results in Table 4). The S. aureus biofilm model predicted much deeper oxygen penetration (~50 μm vs. ~25 μm) due to more efficient use of oxygen for glucose oxidation (Fig. 2b). Superior anaerobic growth allowed S. aureus to produce much thicker biofilms under the same environmental conditions. Otherwise, the predictions were similar to those obtained with P. aeruginosa with lactate replacing succinate as a primary byproduct. If the S. aureus biofilm thickness was chosen larger than Wmax = 90 μm, the biomass concentration dropped below 10 g/L near the top of the biofilm due to inadequate glucose penetration. The effect of the metabolite mass transfer coefficients on concentration gradients within the S. aureus biofilm are shown in Additional file 1: Figure S1.Fig. 2

View Article: PubMed Central - PubMed

ABSTRACT

Background: Chronic wounds are often colonized by consortia comprised of different bacterial species growing as biofilms on a complex mixture of wound exudate. Bacteria growing in biofilms exhibit phenotypes distinct from planktonic growth, often rendering the application of antibacterial compounds ineffective. Computational modeling represents a complementary tool to experimentation for generating fundamental knowledge and developing more effective treatment strategies for chronic wound biofilm consortia.

Results: We developed spatiotemporal models to investigate the multispecies metabolism of a biofilm consortium comprised of two common chronic wound isolates: the aerobe Pseudomonas aeruginosa and the facultative anaerobe Staphylococcus aureus. By combining genome-scale metabolic reconstructions with partial differential equations for metabolite diffusion, the models were able to provide both temporal and spatial predictions with genome-scale resolution. The models were used to analyze the metabolic differences between single species and two species biofilms and to demonstrate the tendency of the two bacteria to spatially partition in the multispecies biofilm as observed experimentally. Nutrient gradients imposed by supplying glucose at the bottom and oxygen at the top of the biofilm induced spatial partitioning of the two species, with S. aureus most concentrated in the anaerobic region and P. aeruginosa present only in the aerobic region. The two species system was predicted to support a maximum biofilm thickness much greater than P. aeruginosa alone but slightly less than S. aureus alone, suggesting an antagonistic metabolic effect of P. aeruginosa on S. aureus. When each species was allowed to enhance its growth through consumption of secreted metabolic byproducts assuming identical uptake kinetics, the competitiveness of P. aeruginosa was further reduced due primarily to the more efficient lactate metabolism of S. aureus. Lysis of S. aureus by a small molecule inhibitor secreted from P. aeruginosa and/or P. aeruginosa aerotaxis were predicted to substantially increase P. aeruginosa competitiveness in the aerobic region, consistent with in vitro experimental studies.

Conclusions: Our biofilm modeling approach allows the prediction of individual species metabolism and interspecies interactions in both time and space with genome-scale resolution. This study yielded new insights into the multispecies metabolism of a chronic wound biofilm, in particular metabolic factors that may lead to spatial partitioning of the two bacterial species. We believe that P. aeruginosa lysis of S. aureus combined with nutrient competition is a particularly relevant scenario for which model predictions could be tested experimentally.

Electronic supplementary material: The online version of this article (doi:10.1186/s12918-016-0334-8) contains supplementary material, which is available to authorized users.

No MeSH data available.


Related in: MedlinePlus