Modeling Polygenic Antibiotic Resistance Evolution in Biofilms

Abstract

The recalcitrance of biofilms to antimicrobials is a multi-factorial phenomenon, including genetic, physical, and physiological changes. Individually, they often cannot account for biofilm recalcitrance. However, their combination can increase the minimal inhibitory concentration of antibiotics needed to kill bacterial cells by three orders of magnitude, explaining bacterial survival under otherwise lethal drug treatment. The relative contributions of these factors depend on the specific antibiotics, bacterial strain, as well as environmental and growth conditions. An emerging population genetic property—increased biofilm genetic diversity—further enhances biofilm recalcitrance. Here, we develop a polygenic model of biofilm recalcitrance accounting for multiple phenotypic mechanisms proposed to explain biofilm recalcitrance. The model can be used to generate predictions about the emergence of resistance—its timing and population genetic consequences. We use the model to simulate various treatments and experimental setups. Our simulations predict that the evolution of resistance is impaired in biofilms at low antimicrobial concentrations while it is facilitated at higher concentrations. In scenarios that allow bacteria exchange between planktonic and biofilm compartments, the evolution of resistance is further facilitated compared to scenarios without exchange. We compare these predictions to published experimental observations.

Alternate Antimicrobial Therapies and Their Companion Tests

“…The minimal selective concentration values do not differ between planktonic cultures and biofilms [118]. In biofilm growth, shifts and distortions to the MSW has been predicted [114]. A promising avenue is to investigate intrinsic heterogeneities of biofilms and hindrance in resistance evolution.…”

“…Resistance in biofilm increases with the continuous exchange of planktonic cells in biofilms. Therefore, it is worth noting that the timing and frequency of dosing influences the dynamics [113,114].…”

The pharmacokinetic–pharmacodynamic modelling framework as a tool to predict drug resistance evolution

“…Biofilms are typically less amenable to AB treatment due to limited penetration of antimicrobial molecules and low metabolic activity of many bacteria in such biofilms [71,142,155,156]. The PKPD framework coupled with population genetic approaches has recently also been successfully applied to biofilms [157,158]. A quite surprising finding of these studies is that, while biofilms allow bacteria to evolve resistance at higher drug doses than for planktonic cells, they also impede resistance evolution at drug concentrations at which planktonic cells will evolve resistance.…”

Infection dynamics in the urinary tract - The importance of non-planktonic phases during early infection and resistance evolution

“…Further, the biofilm-like phase of intracellular growth slows down growth and leads to physiological changes such as a coccoid shape (Sharma et al, 2021). If treated with antibiotics, the permeation of the drug as well as the biophysical properties of the intracellular biofilm-like structure limit the drug exposure of the intracellular bacteria (Singh et al, 2010), while planktonic and attached bacteria are exposed to higher drug concentrations (Trubenová et al, 2022b). Such spatial heterogeneity of the antibiotic selection pressure may facilitate resistance evolution in bacteria (Greulich et al, 2012;Hermsen et al, 2012;Moreno-Gamez et al, 2015;Nicholson and Antal, 2019;Trubenová et al, 2022a).…”