# Cellular Self-Digestion and Persistence in Bacteria
## 1 Introduction  
Antibiotic failure is a growing concern worldwide [1], and persister cells--a small subpopulation of transiently non-growing drug-tolerant cells within a larger bacterial cell population--significantly contribute to this problem by facilitating the emergence of antibiotic-resistant mutants and the recurrence of microbial infections [2, 3, 4, 5, 6]. Because it is not mediated by heritable mutations, the persister state is reversible, and persister formation can occur in response to multiple environmental triggers, including antibiotic treatment [7, 8], nutrient depletion [9, 10, 11], temperature [12], and pH [13, 14, 15]. A number of pathways have been implicated in persister formation, including the SOS response [7, 16, 17], the ppGpp-mediated stringent response [10, 18], quorum sensing [19, 20], and cellular aging [21]. In addition, reactive oxygen species (ROS) [22, 23, 24], toxin/antitoxin (TA) systems [25, 26], and intracellular proteases [15, 27] have been involved in this process. Notably, persistence seems to be a conserved phenomenon that has been reported in many cell types, including cancer cells [28, 29, 30, 31]. Persister cells have been identified in almost every pathogenic or nonpathogenic microbial species studied to date, including _Escherichia coli_, _Acinetobacter humanuiii_, _Cyanobacteria_, _Salmonella Typhimuriumium_, _Vibrio cholerae_, _Xylella fasti-iosa_, _Staphylococcus aureus_, _Mycobacterium tuberculosis_, _Candida albicans_, and _Saccharomyces cerevisiae_[31]. Although dormancy is thought to be the prevailing trait that makes these persister phenotypes tolerant to external stresses [32, 33, 34, 35, 36], a significant number of studies have shown that persister cells are heterogeneous [37, 38, 39, 40, 41, 42, 43, 44, 45, 46] and can escape cell death pathways through a diverse range of epigenetic mechanisms [10, 18, 19, 47, 48, 49]. From an evolutionary perspective, self-digestion, known as autophagy in eukaryotes, is an important survival mechanism. This complex intracellular degradation is coordinated by many regulatory proteins and checkpoint kinases and has been well documented inmammalian cells [50; 51], although rarely studied in bacteria. Autophagic mechanisms are associated with a diverse range of enzymes, including proteases, nucleases, glycosidases, lipases, and phosphatases, which are essential components of the intracellular degradation machineries [52; 53]. Although self-digestion temporarily provides energy to cells in a non-nutritive environment or under stress conditions, this process may result in growth arrest or death due to the degradation of intracellular components. Critically, in some cases, these components are targets of conventional antibiotics. Self-digestion can therefore act as a double-edge sword; while excessive intracellular degradation can eventually result in cell death and the elimination of persisters [27; 54], moderate degradation might only cause growth arrest and may render persisters transiently resistant to antibiotics [55]. Thus, mapping this complex network that may mediate persister formation will not only enhance our knowledge of persister cell physiology, but also provide novel antipersister therapeutic approaches. A number of outstanding reviews on bacterial persister formation/reawakening mechanisms, physiology, evolutionary perspectives, and treatment strategies have been published in the literature to date [31; 44; 56; 57; 58; 59; 60; 61; 62; 63; 64; 65; 66]. Therefore, in this review article, we will particularly focus on the potential links between self-digestion and bacterial persistence. Specifically, we will first discuss the underlying reasons for self-digestion in bacteria and why it is an important survival mechanism, while highlighting the potential degradative mechanisms (including for those protein, ribonucleic acid (RNA), and lipids) that may induce persister cell formation. We will also explore how self-digestion may shape persister cell metabolism.