# Recent Advances in Bacterial Persistence Mechanisms
## 1 Introduction  
In 1944, [PERSON] reported a small number of survivors, namely persisters, for the first time when he was studying staphylococcus treated with intermittent penicillin sterilization. Unlike resistant strains, descendants of persisters are susceptible to penicillin, suggesting that survival ability is inheritable [1]. Since then, an increasing number of reports have indicated that persisters are associated with relapsing infections and can survive therapy in diseases such as tuberculosis and urinary tract infections, despite the susceptibility to antibiotics seen in clinical laboratory tests [2]. Persister is a bacteria subpopulation that grows slowly or in a dormant manner. The state of persistence can be induced by a variety of mechanisms, and their antibiotic susceptibility is generally reduced due to dormancy [3]. This feature of persisters makes them unable to be completely eliminated during antibiotic treatment, which increases the likelihood of resistance and can lead to infection recurrence [4]. It is generally believed that persisters are crucial for pathogens to survive antimicrobial chemotherapy when the host's immune response is limited [5]. The incidence of persister infections is especially high in immunocompromised patients with the human immunodeficiency virus or those undergoing cancer chemotherapy. For example, increased numbers of persister cells of _Pseudomonas aeruginosa (P. aeruginosa)_ are a major concern for immunocompromised and cystic fibrosis patients, leading to high morbidity and mortality [6]. However, in immunocompetent individuals in cases where the pathogen is located at sites poorly accessible by components of the immune system, persister formation is also likely to take place [5]. Consequently, the site of infection would play a role in persister formation.  
With the studies of persistence, a few intracellular bacteria have recently been found to exhibit a persistent phenotype [7]. One of the most distinctive features of persistence is the biphasic killing curve resulting from the coexistence of antibiotic-susceptible and persistent cells [8]. After being exposed to antibiotics, the most susceptible bacteria are rapidly killed,while a small proportion of persisters survive longer in a non-growing state (Figure 1). Once antibiotics are removed, persisters recover to grow and exhibit similar patterns to antibiotic-susceptible bacteria [9; 10]. Besides antibiotics, some other stress environments, such as acid, toxic metals, and high temperatures, can also induce persister formation [11]. Nonetheless, antibiotic-induced persistence is of more concern in the hospital setting. In the clinic, antibiotic treatment is usually administered at regular dosages and times. Therefore, the antibiotic concentration in vivo fluctuates periodically [12]. In long-term treatment patients who received periodic antibiotics of a high concentration, the proportion of persisters in isolated _P. aeruginosa_ was 100 times higher than during the early stages of treatment. However, the minimum inhibitory concentration (MIC) did not change significantly [13]. Accordingly, the failure of antibiotic treatment may not be solely due to resistance, as persistence may also play a role.