## 2 Persistence as an Evolutionary Adaptation  
The term persistence describes the ability of a bacterial subpopulation to survive antibiotic exposure due to non-heritable phenotypic variation that is distinct from the mechanisms that generate resistance [1]. Persisters represent a small fraction of the total cells, but their survival allows the population to survive times of high antibiotic exposure [4]. After stress subsides, persisters revert to an antibiotic-sensitive state, reinitiate growth, and repopulate the local environment. In fact, post-treatment sensitization towards antibiotics is a definitive characteristic of persister cells [9]. This phenomenon is akin to ecological succession, where antibiotic pressure represents a bottleneck event and persisters are the first to subsequently utilize available nutrients and environmental niches. Like a wildfire that decimates a forest, antibiotic exposure wipes out 99 percent of a susceptible community while persister cells survive as a result of their transient antibiotic tolerance. As the sole survivors of antibiotic exposure, these persister cells then function as the pioneer \"species\" in a now-vacant ecological niche and subsequently lose their tolerant phenotype as they repopulate and grow towards a steady state community. In this manner, persistence can be viewed as an evolutionary strategy by which a population assures its survival through a few key members. As an adaptive trait, persistence is heterogeneous and emerges via multiple mechanisms. Persistence has thus been categorized into subtypes for clarification. First, time-dependent persistence is contingent on growth rate reductions within the persister subpopulation that reduce antibiotic uptake and target availability [10]. Time-dependent persistence can be further subdivided into Type I and Type II persistence, where Type I is triggered by a reduced lag time and Type II is triggered by growth rate reduction [4; 10]. Second, dose-dependent persistence is an adaptive response in which transient overexpression of efflux pumps and stress response pathways facilitate survival during antibiotic challenge [4; 10; 11]. The PASH (Persistence As Stuff Happens) model has recently gained popularity and suggests that both time- and dose-dependent persistence are the result of stochastic errors in metabolism, cell division, and stress responses and is thus analogous to spontaneous mutations observed in antibiotic resistance [12]. PASH suggests that persistence is a form of bet-hedging or adaptive behavior in which a small subset of the population exhibits randomized phenotypic variation. The utilization of toxin-antitoxin modules serves as one example of this bet-hedging strategy. Perhaps the best characterized of these systems is the _hipAB_ module in _Escherichia coli_[13]. In this case, _E. coli_ enter into a dormant state once the levels of the _hipA_ toxin exceed a certain threshold [13]. Overexpression of _hipA_ increases the tolerance of _E. coli_ to bactericidal antibiotics [14]. However, these toxin levels fluctuate within a population in the absence of antibiotics, suggesting that they may represent a generalized response that allows bacterial populations to survive sudden stress [13; 14; 15]. Compared to antibiotic resistance, this randomization confers a selective advantage with a significantly diminished fitness cost and reduced need for compensatory adaptations [16]. [PERSON] et al. recently aimed to identify whether persistence and resistance represent complementary, albeit divergent, survival strategies that bacteria have co-opted to survive antibiotic and environmental stressors [17]. After challenging various _Pseudomonas_ species with ciprofloxacin and rifamp, they found that persistence and resistance generation were mechanistically unrelated but positively correlated, suggesting that they represent complementary, rather than competitive, evolutionary strategies [17]. Persistence is a plastic trait, while resistance is genetically encoded.