Phenotypic-dependent variability and the emergence of tolerance in bacterial populations

Ecological and evolutionary dynamics have been historically regarded as unfolding at broadly separated timescales. However, these two types of processes are nowadays well-documented to intersperse much more tightly than traditionally assumed, especially in communities of microorganisms. Advancing the development of mathematical and computational approaches to shed novel light onto eco-evolutionary problems is a challenge of utmost relevance. With this motivation in mind, here we scrutinize recent experimental results showing evidence of rapid evolution of tolerance by lag in bacterial populations that are periodically exposed to antibiotic stress in laboratory conditions. In particular, the distribution of single-cell lag times-i.e., the times that individual bacteria from the community remain in a dormant state to cope with stress-evolves its average value to approximately fit the antibiotic-exposure time. Moreover, the distribution develops right-skewed heavy tails, revealing the presence of individuals with anomalously large lag times. Here, we develop a parsimonious individual-based model mimicking the actual demographic processes of the experimental setup. Individuals are characterized by a single phenotypic trait: their intrinsic lag time, which is transmitted with variation to the progeny. The model-in a version in which the amplitude of phenotypic variations grows with the parent's lag time-is able to reproduce quite well the key empirical observations. Furthermore, we develop a general mathematical framework allowing us to describe with good accuracy the properties of the stochastic model by means of a macroscopic equation, which generalizes the Crow-Kimura equation in population genetics. Even if the model does not account for all the biological mechanisms (e.g., genetic changes) in a detailed way-i.e., it is a phenomenological one-it sheds light onto the eco-evolutionary dynamics of the problem and can be helpful to design strategies to hinder the emergence of tolerance in bacterial communities. From a broader perspective, this work represents a benchmark for the mathematical framework designed to tackle much more general eco-evolutionary problems, thus paving the road to further research avenues.</p> Author summary Problems in which ecological and evolutionary changes occur at similar timescales and feedback into each other are ubiquitous and of outmost importance, especially in microbiology. A particularly relevant problem is that of the emergence of tolerance to antibiotics by lag, that has been recently shown to emerge very fast in bacterial (E. coli) populations under controlled laboratory conditions. Here, we present a computational individual-based model, allowing us to reproduce empirical observations and, also, introduce a very general analytical framework to rationalize such results. We believe that our combined computational and analytical approach may inform the development of well-informed strategies to mitigate the emergence of bacterial tolerance and resistance to antibiotics and, more generally, can help shedding light onto more general eco-evolutionary problems.</p>