1. Introduction
Acinetobacter baumannii is a pathogen responsible for infections that are extremely problematic in hospitals. It has no typical virulence factors such as toxins to explain its pathogenicity [1]. Therefore, this pathogen has been referred to have a ”persist and resist” virulence strategy [2]. This means that it is capable of surviving in very hostile environments [3]. More particularly, this bacterium is well known for its resistance to desiccation, its ability to form a biofilm to protect itself from external stresses and also its capacity to develop easily antibiotic resistances, notably to the carbapenem class [4], [5], [6]. The difficulty of eradicating this bacterium makes it particularly dangerous when found in a hospital environment[7]. Consequently, it has been classified in the “Priority 1” pathogen group by the World a Health Organization in 2017 - this status was confirmed in 2024 - to prioritize the development of new antibacterial agents [W1]. This phenomenon of multi-resistance, becoming increasingly widespread, is the root of many therapeutic failures [8], [9]. Persister cells in bacteria were first described by Hobby in 1942 and Joseph Bigger in 1944 [10], [11]. Persister cells are a bacterial subpopulation able of surviving to high concentrations of antibiotics compared to isogenic individuals [12], [13]. Recently, it was shown that phages also produce a subpopulation of persister cells similar to those generated/selected by antibiotics [14].
This recalcitrant phenotype is reversible and thus temporary since persister cells are able to regrow after the removal of selection pressure, to reform a population similar to the original, i.e. susceptible to antibiotics [13]. Persister cells are generally characterized by a growth arrest. However, it seems that this feature is neither necessary nor sufficient to enter into persistence [15]. Two types of persister cells have been described (Figure 1) [12]. One is the result of a spontaneous formation and are cells, very poorly represented in a population, which do not present a response to any particular stress but which can enter into a very slow multiplication phase even under favorable conditions (Figure 1A) [16]. The other type, the triggered persister, formerly called type I [16] is generated by an environmental stressor like a late stationary phase starvation [17], a high cell density [18] , or an antibiotic exposure[12] (Figure 1B). It should be noticed that the viable but non-culturable cells (VBNC) could sometimes be considered as persister exhibiting a longer latency [19]. The VBNC remain intact and metabolically active after exposure to an antibiotic, but unlike persister cells, they can not resume growth after antibiotic removal [20]. However, it has been shown that under certain conditions, some VBNC could regrow with a transcriptomic profile very similar to the one of persister [19]. Two main methodologies are available for studying persister cells: the study at individual cell level using microfluidics, growth reporters and ScanLag as examples or the study of the subpopulation level via genetic screens, evolution of whole genome sequencing, -omics techniques or mathematical modeling ..etc [21], [22], [23], [24]. These have been used to highlight some mechanisms involved in the formation or in the selection or that may play a role in the physiology of persister cells, like the toxin-antitoxin systems, some second messengers activating specific transcription factors, the activation of the SOS response, the oxidative stress response and the membrane modifications. It is still difficult to determine whether these mechanisms are directly or indirectly involved, whether they are a cause or a consequence, but they play a role in the physiology of persister cell.
It is admitted that persister cells can represent up to 10 % of the cells living in biofilm mode and <1 % of the cells in planktonic growth mode [25]. As they might be partly responsible for the recurrence of chronic infections [26], [27], [28] and could also promote resistance mechanisms development [29], [30], the “persister” field of research is increasingly being explored. In this review, we bring together the main findings about the molecular mechanisms by which persister cells of A. baumannii could appear or that are involved in their physiology, and which molecules may be used to prevent their appearance or destroy them.