Mathematical modeling of dormant cell formation in growing biofilm

Abstract

Understanding the dynamics of dormant cells in microbial biofilms, in which the bacteria are embedded in extracellular matrix, is important for developing successful antibiotic therapies against pathogenic bacteria. Although some of the molecular mechanisms leading to bacterial persistence have been speculated in planktonic bacterial cell, how dormant cells emerge in the biofilms of pathogenic bacteria such as Pseudomonas aeruginosa remains unclear. The present study proposes four hypotheses of dormant cell formation; stochastic process, nutrient-dependent, oxygen-dependent, and time-dependent processes. These hypotheses were implemented into a three-dimensional individual-based model of biofilm formation. Numerical simulations of the different mechanisms yielded qualitatively different spatiotemporal distributions of dormant cells in the growing biofilm. Based on these simulation results, we discuss what kinds of experimental studies are effective for discriminating dormant cell formation mechanisms in biofilms.

Mesoscopic Energy Minimization Drives Pseudomonas aeruginosa Biofilm Morphologies and Consequent Stratification of Antibiotic Activity Based on Cell Metabolism

“…We have therefore developed two-substrate Tessier kinetics for modeling the biofilm growth from uptake of oxygen and glucose ( Table 1 ). Our model based on Tessier kinetics is a more accurate predictor of the proliferation rate of bacterial cells than are previous P. aeruginosa biofilm simulations ( 25 , 27 – 29 ); the proliferation rate is an important parameter for transformation of cells from an active state to a dormant state. …”

“…This observation suggests that the macroscopic biofilm structure is actively changed by microscopic interactions between individual bacteria and is not a passively evolved structure due to nutrient gradients. However, extensive studies considering interaction forces between the bacteria and nutrient limitations were unable to predict the formation of the observed complex 3D mushroom shapes ( 21 – 25 ). Typically, these studies predicted a series of hemispherical shapes but were not able to predict the mushroom shapes observed in nature, specifically with those involving wild-type bacteria.…”

“…Glucose is present in excess in both the experiments and the numerical models. Single-solute Monod kinetics is the common choice in most biofilm models ( 25 , 27 – 29 ). This, however, would result in exponential cell growth in the simulations due to the presence of excess nutrients.…”

Microbial Controls on the Biogeochemical Dynamics in the Subsurface

“…Alternatively, a switch function that depends on environmental conditions can be used to determine the direction of the transition (Stolpovsky et al 2011;Mellage et al 2015;Bradley et al 2018a). Other concepts consider both, deactivation (Chihara et al 2015) and reactivation (Epstein 2009;Buerger et al 2012) to be random processes, or rely on a growth rate dependent dormancy index to determine the fraction of dormant bacteria (Wirtz 2003). Furthermore, different degrees of dormancy may be considered assuming either distinct subgroups of dormant microorganisms or considering the depth of dormancy to increase with the duration of the unfavorable conditions (Stolpovsky et al 2011).…”

Structural and metabolic responses of Staphylococcus aureus biofilms to hyperosmotic and antibiotic stress

“…This switch from aerobic respiration to anaerobic fermentation is relevant to antibiotic resistance (Martínez & Rojo, 2011), the transcription of virulence genes (Fuchs et al, 2007), as well as the expression of extracellular polysaccharides involved in cellto-cell adhesion and biofilm formation (Cramton, Gerke, Schnell, Nichols, & Gotz, 1999;Cramton, Ulrich, Gotz, & Doring, 2001). In addition, oxygen can be scarce near the bottom of biofilms (Cotter, O'Cara, & Casey, 2009), which may indicate dormancy of cells near the bottom layer, proximate to the substratum, and a fermentative metabolism (Chihara, Matsumoto, Kagawa, & Tsuneda, 2015). These processes can be determined if a specific metabolite is present in the biofilm.…”