Bistable Bacterial Growth Dynamics in the Presence of Antimicrobial Agents

Abstract

The outcome of an antibiotic treatment on the growth capacity of bacteria is largely dependent on the initial population size (Inoculum Effect). We characterized and built a model of this effect in E. coli cultures using a large variety of antimicrobials, including conventional antibiotics, and for the first time, cationic antimicrobial peptides (CAMPs). Our results show that all classes of antimicrobial drugs induce an inoculum effect, which, as we explain, implies that the dynamic is bistable: For a range of anti-microbial densities, a very small inoculum decays whereas a larger inoculum grows, and the threshold inoculum depends on the drug concentration. We characterized three distinct classes of drug-induced bistable growth dynamics and demonstrate that in rich medium, CAMPs correspond to the simplest class, bacteriostatic antibiotics to the second class, and all other traditional antibiotics to the third, more complex class. These findings provide a unifying universal framework for describing the dynamics of the inoculum effect induced by antimicrobials with inherently different killing mechanisms.

Eugenol-Functionalized Magnetite Nanoparticles Modulate Virulence and Persistence in Pseudomonas aeruginosa Clinical Strains

“…The results of the evaluation of persister cell production show that the used nanomaterials may influence this phenotype, but the results are strictly influenced by the dose, the resistance profile of microbial cells, and the utilized antibiotic. Our results cannot be extrapolated for other antibiotics, because exposure time or culturing conditions may vary, mainly due to bacteria bistability [39,42] and other less-known factors. However, our results reveal that NPs could potentiate the effect of eugenol on persister population selection, highlighting the utility of hybrid nanosystems, based on natural products and inorganic NPs, to reduce the selection of resistant cells under antibiotic pressure.…”

“…As a result of external pressure exhibited by antibiotics and other chemicals affecting the fitness of the microbial population in both planktonic and biofilm growth states, a subpopulation with a changed metabolism and different behavior that aims to resist to the stressor agent can be selected, despite the identical genotype of all bacterial cells of the exposed population. This behavior is considered an epigenetic switch and is called bacteria bistability [37][38][39]. The bacterial cells resisting the action of antimicrobial substances enter a slow metabolic state and are called persisters or persistent cells.…”

Interplay between strain fitness and transmission frequency determines prevalence of antimicrobial resistance

“…This is why experimental data with controlled variables could be a valuable first step in validating the theoretical models. Indeed, in vitro validation has been possible for many within-host models (e.g., Alexander and MacLean, 2020;Frenkel et al, 2021); yet, this is not the case for between-host models. It is laborious, time-consuming and expensive to reproduce a population of hosts in the laboratory, and therefore it is critical to establish the range of values that should be explored (or not) for each parameter beforehand.…”

Probing the Gelation Synergies and Anti-Escherichia coli Activity of Fmoc-Phenylalanine/Graphene Oxide Hybrid Hydrogel

“…This could be explained by the “ inoculum effect ” (IE), in which the antimicrobial outcome of a bactericidal depends on the initial population size. 39 Several mechanisms related to the IE, such as the “ phenotypic heterogeneity ” and “ bacterial density ”, may affect the cell–hydrogel interactions. Therefore, the abrupt bacterial death (in our case within the first 5 h of incubation) is followed by the regrowth of the surviving bacteria, on which the hydrogels do not have an effect due to the IE.…”

“…Although the bacterial growth was delayed for the first 5 h of incubation and a large number of cells died, the remaining ones developed resistance over time and managed to increase their population density compared to the untreated cells. This could be explained by the “ inoculum effect ” (IE), in which the antimicrobial outcome of a bactericidal depends on the initial population size . Several mechanisms related to the IE, such as the “ phenotypic heterogeneity ” and “ bacterial density ”, may affect the cell–hydrogel interactions.…”