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.