An ecological and stochastic perspective on persisters resuscitation

Resistance, tolerance, and persistence to antibiotics have mainly been studied at the level of a single microbial isolate. However, in recent years it has become evident that microbial interactions play a role in determining the success of antibiotic treatments, in particular by influencing the occurrence of persistence and tolerance within a population. Additionally, the challenge of resuscitation (the capability of a population to revive after antibiotic exposure) and pathogen clearance are strongly linked to the small size of the surviving population and to the presence of fluctuations in cell counts. Indeed, while large population dynamics can be considered deterministic, small populations are influenced by stochastic processes, making their behaviour less predictable. Our study argues that microbe-microbe interactions within a community affect the mode, tempo, and success of persister resuscitation and that these are further influenced by noise. To this aim, we developed a theoretical model of a three-member microbial community and analysed the role of cell-to-cell interactions on pathogen clearance, using both deterministic and stochastic simulations. Our findings highlight the importance of ecological interactions and population size fluctuations (and hence the underlying cellular mechanisms) in determining the resilience of microbial populations following antibiotic treatment.