Preservative Kinetics and Influence of Surfactants on Gram-Negative Bacterial Membrane Partitioning

Preservatives are primarily used for their antimicrobial properties and form an important component of food, cosmetic, and drug formulations. The efficacy of preservatives depends on various factors, which include the bacterial membrane composition and the interaction between components of a specific formulation. Molecules such as phenoxyethanol (POE), caprylylglycol (CPG), and methylparaben (MEP) are widely used as preservatives in the food and cosmetic industries; however, a molecular understanding of their interactions with surfactants and the kinetics of membrane partitioning remains unexplored. In this study, coarse-grained molecular dynamics simulations were carried out to evaluate and quantify the kinetics of membrane partitioning for preservatives and surfactants in the Escherichia coli inner phospholipid membrane. We propose a mass-transfer-based model to determine membrane partitioning kinetics. Faster kinetics were observed for first-order partitioning of POE and MEP (τ ∼ 0.01 μs) when compared with zeroth-order kinetics (τ ∼ 0.1 μs) for CPG. In contrast, surfactants such as sodium laureth sulfate (SLES) and cocamidopropyl betaine (CAPB) follow zeroth-order membrane partitioning kinetics with significantly higher time constants (1.5-10 μs). Interestingly, zeroth-order kinetics occurred when micellar aggregates were present, and the rate-controlling step was the slow rate of release of single molecules from the aggregate, in comparison to faster membrane uptake kinetics. Using a sequential micellar breakup model with single surfactant release dynamics, we analytically recover this unique zeroth-order membrane partitioning kinetics. In preservative-surfactant mixtures, the kinetics of preservative partitioning were found to decrease by a factor of 2-10. Significantly, the equilibrium membrane saturation coefficients for both preservatives and surfactant remained invariant in the mixtures due to the wide separation of partitioning time scales for the surfactants and preservatives. The kinetic models developed in this study can be used to quantify membrane partitioning of preservatives and understand the influence of surfactants in specific formulations.