Beyond metabolic dormancy: metabolic rewiring in bacterial persistence

Bacterial persister cells that exhibit a transient state of antibiotic tolerance play a key role in chronic and recurring infections. Despite advances in our understanding of persisters, many aspects of their phenotypic plasticity, particularly their metabolism, are poorly characterized. In this Perspective, we examine the static and dynamic characteristics of persister metabolism that are shaped by genetics, environmental cues, and the intrinsic variability in cellular processes. These factors underlie much of the diversity observed among persister cells and largely explain the inconsistency in expression of classic persister hallmarks such as biphasic killing curves or metabolic dormancy. Further, the literature suggests that persisters are not uniformly metabolically dormant but represent a range of metabolic states. We will focus on the unique rewiring of the metabolic mechanisms in persisters, which depends on both internal and external factors. Bacterial persister cells exhibit a transient state of antibiotic tolerance and are commonly assumed to be metabolically ‘dormant’. In this Perspective, Orman et al. re-examine common assumptions and emphasize that persisters represent a range of metabolic states, driven by internal and external factors, which may explain the inconsistent expression of classic persister hallmarks.