KEYWORDS: persistence, resistance, respiratory infection, tolerance, treatments, gastrointestinal infection

General Stress Response (RpoS-Mediated Response)

RpoS and the other general stress responses are important molecular mechanisms whereby bacteria survive stress conditions (7). TherpoS gene encodes the sigma factor (S), which regulates the response (18) to conditions of stress, causing the accumulation of RpoS as cells enter the stationary phase and a rise in the number of related bacteria. RpoS-dependent gene expression leads to global bacterial stress resistance. Specific small RNAs (sRNAs) that encourage RpoS translation or the induction of antiadaptors that make this protein stable are induced in response to several stressors (19).

In isolates of the aforementioned gastrointestinal tract pathogensE. coli andSalmonella enterica serovar Typhimurium, RpoS and the general stress response have important roles in virulence, biofilm development, and bacterial survival. Under conditions of environmental stress or as cells enter the stationary phase,E. coli causes accumulation of RpoS (18,19). RpoS mainly regulates genes and structural proteins associated with the formation and degradation of biofilms in response to stress (18). Several conditions can induce the general stress response in this pathogen, including nutrient deprivation, variations in temperature, biofilm production, high pH, oxidative stress, and other signals (20). In addition, the RpoS response and TA systems interact inE. coli (Fig. 2); for example, the antitoxins MqsA of the MqsR/MqsA TA module and DinJ of the YafQ/DinJ TA repressrpoS transcription and translation, respectively, until stress is encountered and the antitoxins are degraded (21,22). In relation toS. Typhimurium, RpoS and the general stress response system also have a role in virulence or biofilm formation (23). RpoS levels are higher during the stationary phase or whenever bacteria are exposed to stress conditions (24).

On the other hand, whenVibrio cholerae colonizes the human gastrointestinal tract, RpoS regulates a system known as the “mucosal escape response.” In this pathogen, RpoS expression is linked to an increase in the (p)ppGpp alarmone (Fig. 2), managing to improve motility and chemotaxis and presumably contributing to evasion of the mucosal response (25).

In clinical isolates ofKlebsiella pneumoniae, a c-di-GMP phosphodiesterase protein controls the oxidative stress response andin vivo virulence, which is decreased byrpoS and/or bysoxRS deletion, implying RpoS- or SoxRS-dependent control (26).

InShigella flexneri andShigella boydii, acid and base resistances are dependent on pH and are controlled by RpoS under stress conditions. For both types of resistance, the RpoS demand can be overcome by growth under anaerobic and moderately acidic conditions (27–30).

Interestingly, although RpoS is vital for the general stress response in numerous bacteria, it appears to be lacking in some pathogens, and it is not known whether other proteins carry out the same functions.Helicobacter pylori possesses alternative regulatory systems that were not observed until now because of the global response under stress conditions in isolates lacking the classic regulators. Proteins such as Fur and HspR compensate for the absence of RpoS (31). Three proteins associated with the stress response have been described forEnterococcus faecalis: (i) a general stress protein (gsp65), encoded by the hydroperoxide resistanceohr gene, which is induced in response to hydrogen peroxide, heat shock, acid pH, detergents, ethanol, sodium chloride, andtert-butylhydroperoxide (tBOOH) (32); (ii) the gsp62 protein, associated with the reaction to heat shock, acid pH, detergents (i.e., SDS or bile salts), ethanol, tBOOH, sodium chloride, and, to a lesser extent, hydrogen peroxide (33); and (iii) the gls24 protein, implicated in resistance to bile salts and virulence (34–36). Nevertheless, the RpoS protein did not seem to have a role in expression of the genes associated with the pathogenesis ofYersinia enterocolitica infection; however, the RpoS protein was required byY. enterocolitica grown at 37°C to survive a variety of types of environmental stress (37) and hostile environments (38). Analysis of theC. jejuni NCTC 11168 genome sequence demonstrated that RpoS is absent in this organism. In addition, in a study searching for an RpoS homologue in the NCTC 11351 strain ofC. jejuni, the authors concluded that no such homologue was found (39). The absence of an RpoS homologue was confirmed forC. jejuni NCTC 11351 by the lack of induction of stress resistance in the stationary phase (39). The gastrointestinal pathogenClostridium also lacks RpoS. Proteins such as HSP and those comprising the GroESL and DnaKJ systems have been associated with the reaction to chemical stress, whether from autologous metabolites or allogeneic toxic chemicals (e.g., derived carboxylic acids), high H⁺ concentrations (low pH), antibiotics, or solvents (ethanol and butanol), all of which can have a major role in survival of the cells (40).

The important role of RpoS has also been described for respiratory pathogens, e.g.,P. aeruginosa. In this bacterium, RpoS has been shown to positively affect thepls locus, which encodes enzymes that generate an extracellular polysaccharide involved in biofilm formation/expression (41).

However, other factors have been analyzed in pathogens such asS. aureus andB. cenocepacia. ForS. aureus, the σ^B factor has been shown to be involved in the survival of cells under heat as well as electric and hydrostatic pressure (42). ForB. cenocepacia, the importance of two sigma factors (other than RpoS), RpoN (AK34_313) and RpoE (AK34_2044), which are upregulated in thefixLJ deletion mutant relative to those inBurkholderia strain AU0158, has been studied. These sigma factors are critical for the survival ofB. cenocepacia inside macrophages, and RpoN has been found to be essential for biofilm production (43–45).

Oxidant Tolerance (ROS Response)

Reactive oxygen species (ROS) are chemically reactive chemical species with oxygen (hydrogen peroxide [H₂O₂], superoxide [O²⁻], and hydroxyl radical [OH⁻]). In a biological context, ROS are produced as a natural response to the normal metabolism of oxygen and have important functions in cell signaling and homeostasis. Nevertheless, during times of environmental pressure (e.g., UV, heat, or drug exposure), ROS levels can rise. This can produce DNA damage, lipids, and proteins that cause cell death (46–48). Superoxide dismutase (SOD) and catalase enzymes or other antioxidant agents, such as glutathione and vitamin C, can eliminate ROS. When an imbalance between the mechanisms of production and elimination of ROS occurs, with an increase in the former, cells are subjected to oxidative stress (49).

In drug-tolerantE. coli cells, SOD and catalase have been shown to have a protective function (50). In other gastrointestinal pathogens, such asS. Typhimurium, many genes must be expressed in order to inactivate ROS, in a process controlled by regulons, such as SoxRS, OxyR, σS, σE, SlyA, and RecA, as well as the Dps protein, which halts bacterial growth under the control of the σ factor RpoS (51) (Fig. 2). The ROS response favors intestinal inflammation, thus allowing this microorganism to spread in the gut (52).

Interestingly,V. cholerae can generate two types of catalases, KatB and KatG, to promote ROS homeostasis (53). Moreover, inV. cholerae, the transcriptional regulator OxyR is critical for antioxidant defense and enables the microorganism to scavenge environmental ROS to facilitate population growth (54). For this pathogen, the importance of the role of the ROS response in mediating the cholix toxin, a virulence factor that displays the action of ADP-ribosyltransferase on eukaryotic elongation factor 2 of host cells and leads to cell death, was recently demonstrated (55).

On the other hand,K. pneumoniae pyogenic abscess isolates often contain heavy capsular polysaccharides (CPS) and escape phagocytosis or death due to the action of serum factors (56,57), oxidative stress, and the ROS response (58,59). The thick, viscous CPS also control bacterial colonization and biofilm production at the infection location (60).

H. pylori induces chronic inflammation of the stomach epithelium and evades clearance via numerous factors, such as adhesion, cell motility, and detoxification of ROS and toxins (61). AllH. pylori strains encode catalase and SOD proteins to detoxify ROS, andH. pylori arginase limits NO production via macrophage-, neutrophil- and epithelial cell-derived nitric oxide synthase (62,63).

Characterization of ROS detoxification enzymes, such as KatA, SodB, AhpC, Tpx, and Bcp, inC. jejuni has demonstrated the value of these cellular defense systems for the survival of this pathogen against ROS (64). During host colonization,C. jejuni is subjected to damage caused by ROS produced by the host immune system and the gut microbiota. However,C. jejuni possesses important ROS detoxification methods that allow it to outlive and colonize the host (64).

Some interesting features of the ROS response have also been described for other gastrointestinal bacteria, such asShigella dysenteriae,Yersinia enterocolitica, andClostridium difficile. TheShigella dysenteriae 1 toxin produces intestinal infection via a decrease in the endogenous intestinal protection against ROS (65). Two new SODs associated with survival in acidic environments, including that in intraphagocytic vesicles, have been described forYersinia enterocolitica (66). The siderophore yersiniabactin increases the virulence ofY. enterocolitica and blocks the development of the ROS response through eukaryotic cells (leukocytes, monocytes, and macrophages) (67). Finally, in a study of the distribution of the main enzymes inClostridium involved in antioxidative defense, i.e., SOD and catalase, the physiological responses (induction of SOD and catalase) to factors triggering oxidative stress in the cells of strict anaerobes were shown to be responsible for the ability of the bacteria to remain viable under aerobic conditions (68). Moreover, studies of the induction of ROS by TcdA and TcdB toxins have dissected pathways contributing to this event, and there is speculation about the role of ROS in mediating pathogenesis (69).Clostridium difficile manages oxidative stress efficiently, and survival of this anaerobic microorganism is therefore consistent with ROS being mediated by TcdA and TcdB and thus favoring inflammation (69). On the other hand, the enzyme glutamate dehydrogenase (essential for growth ofC. difficile) participates in the production of alpha-ketoglutarate, which contributes to H₂O₂ tolerance associated with the ROS response (69).

It was recently demonstrated that heterogeneous respiratory bacteria, such as methicillin-resistantS. aureus (MRSA) strains, can exist as two populations, with a heteroresistant phenotype (HeR-MRSA) and a homoresistant phenotype (HoR-MRSA), which are induced by β-lactam antibiotics via oxidative stress and mediated by the ROS response and DNA damage (Fig. 2) (70). The production of ROS during β-lactam treatment seems to be regulated by catalases and dismutases (SODs), which protect organisms with the heteroresistant phenotype from cell death and encourage cell survival. Moreover, disabling the tricarboxylic acid (TCA) cycle activity has a negative effect on ROS production, showing the role of metabolic modifications in the homoresistant phenotype (70). Finally, mutagenesis stimulated by β-lactams in cells with the heteroresistant phenotype demonstrates the conjunction of ROS production and the SOS-induced response (70). On the other hand, conservation of the persistent state in biofilms produced by several pathogens has been associated with adaptation of metabolic processes, mainly the processes associated with ROS formation and the TCA cycle. In addition to the characteristics of cells associated with biofilm production, metabolic changes are also important, as confirmed by survival studies with planktonicS. aureus cells. The appearance of mutants without the TCA cycle enzymes succinate dehydrogenase and aconitase suggests an improved level of survival in the stationary phase (71,72). The decrease in ROS formation was determined to be a fundamental characteristic at this point. The ROS response appears to be associated with programmed cell death inS. aureus strains (73).

SOD and catalase have been analyzed inP. aeruginosa, and thesodB gene has been connected with an important protective role against UV-C radiation (74). The same researchers also found that levels of the POX enzyme increased under stress tolerance (74). According toin vitro evidence, the environmental factors that trigger the selection of mucoid colonies are oxidative stress, low oxygen concentrations, and high osmolarity, i.e., conditions commonly found in the lungs of infected patients. Alginate overproduction confers resistance to phagocytosis but also appears to increase the sensitivity toward β-lactams and other types of antibiotics (75,76) and contributes to the persistent inflammation of the airways (77). The parameters associated with mucoid transition in patients include persistence of bacteria in the sputum and the use of inhaled bronchodilators and inhaled antibiotics, such as colistin (78). A connection between the QS system and the expression of catalase and dismutase proteins in the ROS response of this pathogen has been described (Fig. 2) (79).

Four catalases (KatA, KatE, KatG, and KatX) have been described forAcinetobacter spp., among which KatE is the most effective in the resistance to H₂O₂ (80). In total, 107 differentially expressed proteins have been identified inAcinetobacter baumannii in relation to oxidative stress and are mainly involved in signaling, supposed virulence factors, and the stress response (including oxidative tolerance) (81). Interestingly, oxidant-tolerant cells of this pathogen showed a higher survival rate in response to several bactericidal antibiotics (41,81).

Persistence is decreased inB. cenocepacia mutants lacking catalase or SOD proteins (82). The results obtained by Van Acker and colleagues have contributed greatly to our comprehension of the molecular machinery controlling antimicrobial tolerance in biofilms formed by theBurkholderia cepacia complex, revealing that these biofilms carry tolerant and persistent cells (83). The TCA cycle was downregulated in the remaining persistent cells, which thus prevented ROS production (detoxification). At the same time, the persistent cells switched on a different pathway, the glyoxylate shunt, which may become a new target for therapy. The aforementioned study also demonstrated that treatment ofB. cenocepacia with tobramycin induces ROS production and that persister cells depend on ROS detoxification mechanisms, while processes responsible for ROS production (e.g., the TCA cycle, processes resulting in the production of NAD or flavin adenine dinucleotide, and the electron transport chain) are downregulated in persister cells (83).

Mycobacterial persister development under isoniazid pressure was related to the stochastic difference in the pulsatory expression of KatG, a catalase peroxidase needed for processing and activation of the drug. Slow-pulsing cells processed smaller amounts of the drug and therefore survived longer than fast-pulsing bacteria (84). The persister subpopulation of mycobacteria shows a different type of sensitivity to hydroxyl radicals due to their tolerance to antimicrobials, unlike the larger population, which is susceptible to them. There is increasing agreement on the importance of ROS and oxidative damage in antimicrobial tolerance in other populations resistant to antimicrobial elimination, and the crucial function of ROS in a stochastic persistent subpopulation pattern has been demonstrated for this pathogen (85). However, stress promotes other metabolic pathways in mycobacteria, leading to reduced levels of ROS and increasing the limit for antibiotic-mediated death (86).

Finally, several compounds induce the ROS response in gastrointestinal pathogens, leading to the development of tolerant populations and thus favoring colonization and bacterial pathogenesis, as follows. (i) Salicylate can induce tolerance inE. coli by generation of ROS. Salicylate-induced ROS cause a decrease in the membrane potential, reduce metabolism, and lead to increased tolerance of ROS (87). (ii) Iron is important for pathogenic bacteria, such asS. Typhimurium. Free cytoplasmic iron is used in the formation of radicals and can stimulate the antimicrobial actions of ROS. It has been shown that mice with deficient levels of this metal have a lower risk of developingS. Typhimurium infection (88). (iii) AlthoughSalmonella does not produce indole, when it uses the indole produced by other bacteria, its tolerance of antibiotics increases (52). (iv) Antibiotics such as vancomycin and penicillin may have an impact. The dependence ofEnterococcus spp. on SOD for tolerance of vancomycin and penicillin is usual for antimicrobial-susceptible enterococci (89). (v) A demonstration of the response to ethanol-induced stress (EIS) inS. aureus strains was provided by the expression of 1,091 genes, of which 291 were upregulated (90). The EIS caused upregulation of genes that promote stress response networks (90), including the ROS response, (p)ppGpp, and TA modules (Fig. 2). The transcriptional profile of MRSA pathogens indicated that they reacted to EIS by entering a state of dormancy and modifying the expression of elements from cross-protective stress response systems in an effort to preserve the preexisting proteins (90).

Energy Metabolism

Regarding energy metabolism, we highlight two mechanisms in relation to tolerant populations. First, cytochromebd is a prokaryotic respiratory quinol:O₂ oxidoreductase that enhances the tolerance of cells to oxidative stress (ROS response) and nitrosative stress conditions. When aerobic metabolism is restricted by oxygen limitation in the cells, the cytochromed complex (encoded by the CydAB operon), one of the terminal oxidases in the respiratory network, predominates (91,92). Overexpression of this operon has been implicated in chlorhexidine (biocide)-tolerant cells (93,94) and in taurine metabolism (93).

Efflux Pumps

Efflux pumps are needed to eliminate toxic elements or to maintain the balance of compounds that are vital for bacterial survival (146). Various researchers recently demonstrated that increased expression of efflux systems is vital for active maintenance of a low intracellular antibiotic concentration, and thus specifically the persister state, in nongrowing, nondividingE. coli cells (147–149). Moreover, an active mechanism can also decrease the concentration of the toxic compound (drug), which raises the drug MIC and thus appears in populations with mixed resistance and tolerance phenotypes (5). The multidrug efflux pumps that participate in tolerance and resistance processes can be upregulated by several signals, such as oxidative stress (ROS response) and QS systems, including the type III secretion system (T3SS), T6SS, and other virulence factors (Fig. 2) (150,151).

In vitro studies withE. coli have demonstrated that paraquat-induced tolerance is reliant on the AcrAB multidrug efflux machinery (152). Moreover, overexpression of this efflux pump was shown to be vital for the active maintenance of a low intracellular antibiotic concentration, and thus the tolerant persister state, specifically in nongrowing, nondividingE. coli cells, suggesting the coregulation of dormancy and active processes for the persistence phenotype (147,153). In addition to the AcrAB system,Salmonella possesses at least 11 multidrug efflux pumps (11,154). Among them, we highlight the following. (i) We first mention the AcrD efflux pump ofS. Typhimurium (57). After inactivation of this pump, variations of expression of several genes involved in metabolism, stress responses, and virulence were detected. For example, a reduction in the expression of genes involved in pathogenesis or those that encode products of metabolism of tricarboxylic acid and purines was observed. The exact same effect was observed for the expression of virulence genes inSalmonella pathogenicity islands (SPI-1, SPI-2, SPI-3, SPI-10, and SPI-18). Levels of fumarate associated with swarming motility were also altered after inactivation of the AcrD efflux pump (11). (ii) The MdtD pump stimulates the efflux of citrate, an iron chelator generated during aerobic metabolism. When this efflux pump is induced by stress, iron is expelled from the cell, thus reducing bacterial growth. Expression of a citrate transporter (IceT) leads to a decrease in the vulnerability to ROS, nitrosative stress, and antimicrobial agents. Stress resistance and antibiotic tolerance are mediated by this protein (IceT) via regulation of metabolism, redox chemistry, and intracellular iron (88). (iii) Finally, in the presence of H₂O₂, the MacAB drug efflux pump protectsS. Typhimurium against ROS by inducing the formation of a compound that confers resistance to extracellular H₂O₂. Another function of this protein is to facilitate the growth ofS. Typhimurium within macrophages (154,155). The functions of efflux pumps in multiresistance and in tolerance and/or persistence under stress conditions are not known for this pathogen.

A new multidrug efflux pump, EmrD-3, was recently discovered inV. cholerae O395 (156).

InK. pneumoniae, the AcrAB efflux pump promotes the development of pneumonia by acting as a virulence agent that fights the innate immune defense in the lung (157). Extreme virulence ofK. pneumoniae isolates was recently found to be associated with increased expression of the AcrAB and OqxAB efflux pumps (158).

InH. pylori, an association between biofilm formation and loss of sensitivity to antibiotics was also detected through the action of two expulsion pumps in the process (159).

A contribution of the Cme ABC efflux pump to antibiotic resistance in isolates ofCampylobacter jejuni has been reported (160). In addition, thecmeA gene, which encodes a multidrug efflux transporter, is upregulated in the presence of deoxycholic acid inC. jejuni wild-type strains relative to that in T6SS-deficient strains, suggesting a relationship between the suppression of proliferation and the role of this efflux pump, regulated by the T6SS (151). The relevance of the T6SS to the adhesion, invasion, and colonization of the host and also to the adaptation to deoxycholic acid was thus confirmed, demonstrating the key role of this system in the pathogenesis ofC. jejuni (151).

Researchers in South Africa recently considered drug resistance, efflux pumps, and virulence characteristics in different species ofEnterococcus that occur in surface waters (161). Most of the isolates had four efflux pump genes (mefA,tetK,tetL, andmsrC) and virulence genes, such as theasa1,cylA,gel, andhyl genes (161).

Moreover, forShigella, we highlight two efflux pumps, as follows. (i) The AcrAB efflux pump has been connected to resistance to bile salts as well as to survival and pathogenicity during host transit and later gastrointestinal infection (162). (ii) The MdtJI efflux pump, which is involved in the extrusion of toxic compounds and allows survival of bacteria within infected macrophages, has been described forShigella (163).

Regarding the transporters, we can highlight the RosA/RosB efflux pump ofYersinia enterocolitica (164). For this pathogen, resistance to new cationic antimicrobial peptides has been described as being due to an ejection pump/potassium antiporter mechanism consisting of the RosA and RosB proteins (164).

Finally, CdeA, a multidrug efflux pump belonging to the MATE family and involved in Na⁺ transport, was identified inClostridium difficile but has not been found to be associated with antibiotic resistance (165).

In respiratory bacteria, such asS. aureus, the expression of the Qac efflux pumps has been associated with increased tolerance to biocides (166). The predominant antibiotic resistance mechanism inP. aeruginosa CF isolates is the overexpression of efflux pumps, particularly those belonging to the RND superfamily.P. aeruginosa has genes for at least 12 of these systems, although we can highlight MexAB, which is involved in tolerance to colistin and biofilm formation (167). Moreover, this efflux pump is associated with the transport of 3-oxo-acyl-homoserine lactones, which are the signals used in cell-to-cell communication (QS) (168). The capacity ofP. aeruginosa infections to persist in the lung regardless of antimicrobial treatment depends on the intrinsic tolerance of the bacterium to antibiotics and the readily acquired resistance to new drugs (169).

InAcinetobacter baumannii, increased biofilm production is associated with overexpression of two efflux pumps: AdeABC and AdeFGH (170–172). Under bile salt pressure,A. baumannii strain ATCC 17978 andA. baumannii clone ST79/PFGE-HUI-1 (a clinical strain lacking the AdeABC efflux pump) overexpress the glutamate/aspartate transporter as well as virulence components associated with activation of the QS system (biofilm, surface motility, and T6SS components) (173).

RND efflux pumps, such as BCAM1945-1947 (RND-9) and BCAM0925 (RND-8), protect the biofilm complex ofB. cenocepacia from tobramycin, while the BCAL1672-1676 (RND-3) pump is important for resistance of biofilms to ciprofloxacin and tobramycin (174).

Finally, little information is available about efflux pumps inM. tuberculosis.

SOS Response

The SOS response is triggered by DNA damage, allowing repair of genetic material to enhance cell survival. The SOS system can be considered an important mechanism of bacterial survival under stress conditions, which are related to other stress responses (7,50,175). The SOS response involves genes that not only affect cellular processes, such as DNA recombination and repair, but also affect pathogenesis, antimicrobial resistance, and biofilm production (176). The proteins that make up the SOS system include a transcriptional repressor called LexA and a DNA-binding activating protein, RecA (177). However, other proteins may be involved.

As mentioned above, the RecA protein positively regulates the SOS system inE. coli (178,179). The SOS system contributes to DNA repair but also induces the development of the type I TA module toxin TisB in a subpopulation ofE. coli (180). Different studies have demonstrated that under these conditions (including treatment with fluoroquinolones), the SOS response encourages the production of persister cells through positive regulation of the expression of the TisB toxin inE. coli (152,175,181). InSalmonella spp., swarming motility, bacterial virulence, and antibiotic tolerance are related, and the bacteria are able to control their motility when DNA damage is present, by means of the SOS induction system (RecA) (176). The lack of the RecA protein inSalmonella enterica impairs the swarming ability and also reduces the capacity of the bacterium to cross the intestinal epithelium (182–184).

Stress response pathways that are crucial for the development and survival ofV. cholerae persister cells, especially the SOS system (RecA), have been found to encourage horizontal gene transfer between microorganisms, thus enhancing resistance (185). Antibiotics such as quinolones activate the SOS response and thus increase the incidence of horizontal transfer inV. cholerae (177). Moreover, this pathogen responds to other antimicrobials, such as aminoglycosides, chloramphenicol, and tetracycline, by stimulating the SOS response (175).

Interestingly, several canonical heat and cold shock proteins inK. pneumoniae strains are upregulated under extreme temperatures (low [20°C] and high [50°C]). Among these proteins, we highlight RecA, although other proteins (GrapE, ClpX, and DeaD) may be involved in the response (186).

DNA damage repair inin vivo colonization byH. pylori requires enzymes, such as RecA and AddAB, which are involved in survival at low pH (187,188).

The RecA protein has also been characterized in relation to DNA damage repair inCampylobacter jejuni (189). On the other hand, plasmids encoding UmuDC-like proteins with SOS function have been located in isolates ofStreptococcus pneumoniae Rx1 andE. faecalis UV202 (190).

SOS proteins, such as topoisomerases, and histone-like DNA binding proteins, such as H-NS, HU, and IFH, which are essential for maintaining bacterial DNA organization, have been investigated inShigella spp. (191). The involvement of H-NS in suppressing DNA repair inShigella spp. after UV irradiation has been described (191). The role of H-NS inYersinia enterocolitica has also been reported (192).

Finally, the features of the SOS response have been studied inC. difficile, and the authors reached the conclusion that the SOS system is related toC. difficile sporulation and that the induction of the SOS system can stimulate biofilm production in this pathogen (193). The same authors also showed that LexA controls the expression of toxin genes, metronidazole resistance, biofilm production, and sporulation (193). The relationship between sporulation and the SOS system was also found inBacillus subtilis, through thesda gene (193). Although this gene is absent inC. difficile (194), Walter and colleagues studied how LexA interactedin vitro with the promoter region of another gene associated with sporulation,sspB (194).

The proportion ofS. aureus mutants (i.e., SCVs that are very tolerant to antimicrobials and that can survive in host cells) is higher in cultures exposed to fluoroquinolones and mitomycin C than in nonexposed cultures, and this was found to be correlated with a larger proportion of mutations (indicated by resistance to rifampin) and followed by stimulation of the SOS DNA damage response (195). These findings indicate that environmental stimulation (e.g., with antimicrobial agents that lower replication fidelity) increases the formation of SCVs by activating the SOS response and thus boosts difficult-to-treat persistent infections (195). It has been found thatStaphylococcus aureus strains can adapt to oxidative stress via a mechanism that produces subpopulations of H₂O₂-resistant SCVs with improved catalase production (196). This occurs through a mutagenic DNA repair pathway that includes RexAB, RecA, and polymerase V (Pol V) (196). The SOS response is more complex inP. aeruginosa than inE. coli due to the participation of two other chromosomal regulators (PrtR and PA0906), which are present in mostP. aeruginosa isolates and other species of the genus, in addition to LexA (197–202). InP. aeruginosa, DNA damage causes autocleavage of LexA by RecA and the elimination of repression of the LexA regulon, as inE. coli (198,201,203). The induction of PrtR-managed genes adversely affects survival during genotoxic stress, decreases antimicrobial resistance, and reduces resistance to oxidant agents (204). In addition, the UmuDpR protein has been demonstrated to suppress expression ofP. aeruginosa SOS genes regulated by LexA (205).

RegardingA. baumannii andAcinetobacter baylyi, several authors have examined the role of the RecA protein and UmuC proteins in repairing DNA damage, and therefore in the cellular defense against pressures produced by agents that damage DNA, antibiotics of various families (ciprofloxacin and tetracycline) (206), and oxidizing elements (207–209). Hemolytic Acb strains have been shown to be significantly more tolerant to UV treatment than nonhemolytic isolates and those belonging to otherAcinetobacter species. This demonstrates the diversity of SOS responses inAcinetobacter strains and may partly explain the emergence ofA. baumannii andAcinetobacter ursingii (210). Moreover, a DNA damage-inducible response has been described and found to promote drug resistance inA. baumannii, especially in stressful environments (211).

Little is known about the role of the SOS response inB. cenocepacia.

Finally, forM. tuberculosis, a regulon including Y-family DNA polymerases (ImuA′ and ImuB), which contributes greatly to damage tolerance (in conjunction with the C-family DNA polymerase DnaE2), has been described (212). Recently reported transcriptomic studies showed that various stress response regulons (e.g., the SOS response) and also different TA genes are positively regulated inM. tuberculosis persisters (213,214). However, for this pathogen, an alternative RecA-independent DNA repair mechanism controlled by a ClpR-like factor has also been reported (215).

QS and Secretion Systems

QS is a bacterial communication network that allows cells to modify their collective behavior through signaling molecules, known as autoinducers, according to changes in the environment favoring the formation of persister cells (7,216,217). This process affects bacterial populations and determines the expression of genes regulating virulence, toxin production, motility, chemotaxis, biofilm production, and bacterial competition (secretion systems [T3SS and T6SS]) (Fig. 2), which may contribute to bacterial adaptation and colonization (218). In this review, we consider proteins from the QS system and secretion systems (T3SS and T6SS) due to their association with the development of persister cells, as described for pathogens such asP. aeruginosa andMycobacterium spp. (219,220). We hypothesize the importance in those pathogens of the relationship between the secretion systems (T3SS and T6SS) and the QS system regarding the development of persister cells. However, further studies of these secretion systems are required to clarify these relationships.

The QS systems described forE. coli include the LuxR homolog (SdiA receptor), LuxS (synthetase), autoinducer-2 (AI-2) and autoinducer-3 (AI-3) systems, and an indole-mediated signaling system (221). A QS system was related to the induction ofE. coli persister cells through an indole molecule that overexpresses OxyR and phage shock regulons, preparing the subset of cells for future stress (222,223). In contrast, other researchers have demonstrated that indole and indole analogs reduce persistence (224–226). Several researchers have investigated the connection between tolerance and persistence mechanisms and phenotypic factors controlled by the QS system. It has been shown that biofilms are often associated with intestinal infections caused byE. coli (18). As the main agent of urinary tract infections (UTIs),E. coli can form biofilms within the bladder epithelial cells and thus evade antibiotic activity (180). The bacterial growth rate determines the sensitivity to some antibiotics, as occurs with ciprofloxacin, and therefore the biofilm cells are protected from the action of these antibiotics when they grow at lower rates (20). Furthermore, biofilm formation inE. coli causes cells to have limited access to nutrients, thus increasing the levels of (p)ppGpp involved in tolerance to multiple drugs (Fig. 2) (227,228). Finally, the QS system in enteropathogenicE. coli (EPEC) controls the activation of the type III secretion system, which participates in the modulation of virulence (229).

Three QS systems have been identified inSalmonella, all of which are formed by a synthase, a receptor, and a signal (221), as follows: (i) the unknown synthase, SdiA, and 3OC8HSL system, which has a motility function and promotes resistance to acids (230); (ii) the LuxS, LsrB, and AI-2 system, involved in expression of the Lsr gene cluster (uptake of AI-2) (231); and (iii) the QseB, QseC, and AI-3 system, which is involved in virulence features, motility ability, and biofilm production (232).

S. Typhimurium produces acyl-homoserine lactone (AHL) and the signaling molecule AI-2. Both molecules are produced and released mainly during exponential-phase growth and are implicated in biofilm formation (52). A recently published study showed that the presence ofin vitro bile salts increases the killing of other bacteria byS. Typhimurium in the gut. This antibacterial activity is not efficient against all commensal bacteria. WhileS. Typhimurium outcompetesKlebsiella oxytoca orKlebsiella variicola, commensal species, such asEnterococcus cloacae,Bacteroides fragilis,Bifidobacterium longum,Parabacteroides distasonis, andPrevotella copri, are not overcome (233). Interestingly,Salmonella enterica and other pathogens present T6SS in association with T3SS, quorum sensing (QS), flagellum production, and QS regulators, which is essential for bacterial pathogenesis (234).

The different types of behavior controlled by QS inVibrio spp., such as bioluminescence, T6SS and T3SS, biofilm production, and motility, make this bacterium an ideal model for studying quorum sensing. The following QS systems have been described forV. cholerae: (i) LuxS, LuxP, and AI-2; and (ii) CqsA, CqsS, and CAI-1. Both of these are related to biofilm production, extracellular polysaccharide formation, and other virulence agents (221,235). QS systems are also involved in theV. cholerae persister phenotype (236). It is well known thatV. cholerae can occur either as planktonic cells or adhered to a biofilm matrix that forms aggregates. As in other pathogens, biofilm production inV. cholerae is regulated by QS. Recent evidence suggests that biofilms are formed during the aquatic and intestinal phases of theV. cholerae life cycle and perform an essential function in environmental and intestinal survival and also in the transmission of infection (237).V. cholerae AlsR (quorum sensing-regulated activator) drives the expression of the acetoin gene cluster in response to glucose, acetate, or another activating signal (238). Furthermore, a model describing the regulation of the acetoin biosynthetic gene cluster by AlsR and AphA according to environmental conditions has been established forV. cholerae (238). In many species ofVibrio, the T3SS and T6SS are strongly associated with QS (239–242).V. cholerae uses the T6SS to compete with the different prokaryotic and eukaryotic cells that it finds in several environments and human hosts. Novel research on the expression of the T6SS indicates that this system may promote the persistence phenotype and the development ofV. cholerae infection through direct opposition of bacterial competitors (243).In vitro studies have demonstrated that theV. cholerae T6SS is expressed by bacteriocins (mucins) and modulated by bile salts, which are modified by the microbiota (244). In relation to these findings, an intact T6SS is necessary forV. cholerae to become established in the guts of infant rabbits (245).

Interestingly, QS inK. pneumoniae is LuxS dependent, and AI-2 autoinducers (246,247) participate in biofilm formation (248). In a study involving genomic extraction and data analysis for isolates ofK. pneumoniae, three conserved regions were distinguished and found to contain T6SS genes, which are controlled by the QS system (249).

H. pylori generates extracellular signaling molecules associated with AI-2, which depends on LuxS function. In turn, this is determined by the growth phase, and production is higher in the mid-exponential phase (250–252). Its genetic variability and the capacity ofH. pylori to develop biofilm, and thus to protect itself from environmental stressors, are responsible for the resistance of this pathogen to the usual treatments, and also for its persistence in human tissues (253).In vitro biofilm production byH. pylori is reflected in several studies (254–257). Moreover, this pathogen can even produce biofilms on the human gastric mucosa (257–260).

The LuxS-homologous protein which participates in the synthesis of AI-2 (a key participant in biofilm formation) has been located forC. jejuni. This bacterium can join to and produce biofilms on different surfaces (160). However, aluxS mutant did not show important changes in the virulence phenotype (CmeABC multidrug efflux pump, cell morphology, or mucin penetration). As mentioned above,C. jejuni possesses an operational T6SS encoded by a complete T6SS gene cluster that forms part of an integration factor located in the genomes of someC. jejuni isolates (261). Moreover, the T6SS participates in tolerance of bile salts and deoxycholic acid (DCA) and in the pathogenicity characteristics of bacteria, such as adhesion and invasion (151).

E. faecalis readily forms biofilms. It is capable of acquiring resistance determinants, such as elements of the QS system (fsrA,fsrC, andgelE) and two glycosyltransferase genes (GTF genes), via horizontal gene transfer encoded byepaI andepaOX, which promote biofilm formation (262). Moreover, thefsr QS component and the GelE protease regulated by QS are involved in gentamicin, daptomycin, and linezolid resistance inE. faecalis biofilms but not planktonic cells (262).

RegardingShigella spp., many authors have searched for multiple factors related to the QS system, including the production of the AI-2 signal, inShigella flexneri (263). Moreover, the connection between T3SS and the QS activation process was described in 2011 (264,265). More recently, it was shown thatShigella sonnei, but notS. flexneri, encodes a T6SS, providing a higher capacity for survival in the intestine (266).

The QS ofYersinia enterocolitica has also been investigated (267). Homologues of the LuxI (AHL synthase) and LuxR (response regulator) protein families have been analyzed for several species ofYersinia. AlthoughY. enterocolitica has a LuxRI pair (YenRI), other species have two pairs (267). Moreover, the same researchers demonstrated the role of QS in swimming- and swarming-type motilities ofYersinia (268). Other investigators have shown that biofilm formation may be inherent inY. enterocolitica. The presence of biofilms greatly increased the minimum inhibitory concentration for bacterial regrowth (MICBR) for all antimicrobials (269).

InClostridium difficile, QS plays a role in toxin synthesis (270) as well as biofilm formation (271). Along with LuxS and SpoOA, flagella and the cysteine protease Cwp84 are important for biofilm formation inC. difficile (271,272).

In vivo experiments have examined the function of quorum detection systems inStaphylococcus aureus (SarA and Agr) in the development of persister cells in various types of infections (221). Agr has been shown to be associated with the formation of the persistence phenotype inS. aureus (273). Mutations of eitheragrCA oragrD, but not RNAIII, showed a rise in persister cell formation in stationary-phase cultures (273) (Fig. 3). InS. aureus, a connection between the modulation of AI-2 and different phenotypes displaying capsule formation, biofilm production, antibiotic resistance, and virulence has been observed (274–276). These findings have been corroborated in both laboratory experiments and animal models infected withS. aureus, in whichluxS controlled biofilm formation by regulating theicaR locus. This regulator is a repressor of theica operon (responsible for producing a polysaccharide composed of β-1,6-linkedN-acetylglucosamine), which is necessary for biofilm formation (275). However, the function of LuxS in regulating the QS inStaphylococcus spp. remains controversial.

Quorum sensing inP. aeruginosa involves at least three functional QS circuits, two of which are controlled byN-acyl-homoserine lactone (HSL) signals (LasI/LasR and RhlI/RhiR) and the other of which is controlled by quinolones (221). Five signals have been identified: AI-2,Pseudomonas quinolone signal (PQS), autoinducer peptides (AIPs), AHLs, and diffusible signal factors (DSFs) (277,278). This system is vital for the colonization and later survival of bacteria during infection, as it coordinates phenotypic changes, especially at the beginning of the infection and during binding to the host cell (279). Expression of QS genes is important in determining the progress of infection (acute or chronic). More than 10% of the genes inP. aeruginosa are controlled by QS, and all of these genes are associated with the production of virulence factors, as well as with biofilm formation, antibiotic resistance, surface motility, and stress response-produced adjustments of the metabolic routes (280–282). Moreover, therpoS gene is known to control the Las system (Fig. 2), which is probably involved in the generation of tolerance to ofloxacin inP. aeruginosa (283). Small molecules spread in the environment (QS signals) can trigger biofilm disintegration. One of the most important factors contributing to the survival ofP. aeruginosa, by generation of resistance or tolerance, is the capacity to develop biofilms bothin vivo andin vitro. Biofilms are more tolerant (up to 4 orders of magnitude) than planktonic cells to several antibiotics, as the antibiotics are less able to infiltrate the deepest parts of the structure and because the low oxygen and nutrient concentrations available to the bacteria at those locations render them metabolically inactive. Moreover, up to 1% of bacterial cells in biofilms are persister cells, which are dormant cells that are not affected by antibiotics (8). This type of cell is abundant in bacterial isolates from the lungs of chronic CF patients (284). In addition to mucoid colonies, SCVs, also known as dwarf colonies, are also commonly isolated fromP. aeruginosa infections. SCVs are small (1 to 3 mm in diameter), form biofilms, attach strongly to surfaces, and display autoaggregative properties due to increased exopolysaccharide production (mainly Pel and Psl polysaccharides but sometimes also alginate) and high rates of production of pili (285). Moreover, these SCVs are usually nonmotile and resistant to several different classes of antibiotics (285).In vitro tests have shown that exposure to sublethal concentrations of antibiotics, such as aminoglycosides, selects for the formation of SCVs; hence, exposure to antibiotics may also trigger the selection of SCVsin vivo. In CF patients, prolonged persistent infections, deterioration of pulmonary function, and increased antibiotic resistance are all correlated with the presence of SCVs in sputum. ForPseudomona aeruginosa, the regulators and growth states involved in H2- or H3-T6SS expression, including quorum sensing and iron depletion, have been analyzed (286,287). Analysis of RsmA-mRNA complexes ofP. aeruginosa by gel shift assay as well as translational and transcriptional fusion led to the identification of 40 genes, distributed in six operons, which are translationally controlled by RsmA (288). RsmA is a negative regulator of these clusters as well as of the coding genes of T6SS-HIS-I related to chronicP. aeruginosa disease. In a process generally overlooked until now, RsmA has been demonstrated to act on most known T6SS genes, indicating that the type VI secretion system is also regulated by AmrZ (288).

The QS system inAcinetobacter spp. comprises the AbaR (receptor) and AbaI (synthase) proteins. These proteins are related to some virulence factors, such as motility, antibiotic resistance, survival properties, and biofilm establishment, inAcinetobacter baumannii and otherAcinetobacter spp. (289,290). InAcinetobacter strain M2 (originally namedA. baumannii and later reclassified asAcinetobacter nosocomialis, due to genomic differences), synthesis of 3-hydroxy-C₁₂-HSL requires AbaI (221). More than one AHL has been found in 63% ofAcinetobacter isolates. Nonetheless, there is no correlation between different AHLs and particular species ofAcinetobacter (291). Deletion of theabaI gene, which is associated with AHL formation, reduced biofilm formation by 30 to 40% relative to that in the wild-type strain (290). However, addition of an exogenous AHL obtained fromAcinetobacter restored biofilm formation in the mutant (292). Moreover, the important role of a new QS enzyme, AidA, in bacterial defense against 3-oxo-C₁₂-homoserine-lactone, an inhibitor of the quorum sensing system (293), was recently analyzed (294). Finally, inA. baumannii clinical strains from clone ST79/PFGE-HUI-1 (which lacks the AdeABC efflux pump) and a modified strain (named ATCC 17978 ΔadeB), the presence of bile salts (a stress condition) induced overexpression of genes involved in biofilm production, the T6SS, and surface motility, which are associated with QS (173).

One or more quorum sensing systems containing a synthase and an acyl-homoserine lactone receptor have been identified for all species ofBurkholderia (295). Two complete quorum sensing systems, known as CciIR and CepIR, were discovered inB. cenocepacia J2315, in addition to a gene encoding a regulator known as CepR2 but lacking a synthase and, finally, a system based onBurkholderia diffusible signal factor (BDSF), known as RpfFBC (296–298). Biofilm formation inB. cenocepacia H111 is highly dependent on BapA, which is a surface protein, and BapR, a regulatory protein. Both thebapA andbapR genes need QS for high levels of expression (299). Moreover, in their study, Aguilar and collaborators reported that BapR is an important protein in relation to the development of persister cells, indicating that this regulator may be a useful target in the production of drugs to prevent the formation of biofilms and persister cells (299).

The complexM. tuberculosis biofilms can produce a subpopulation of drug-tolerant persister cells (300). In addition to persistence against antibiotics, biofilms can also be envisioned as being part of a key persistence strategy ofM. tuberculosis against the host immune system in chronic infections, particularly those that do not display clinical symptoms (301). The QS system ofM. tuberculosis is largely unknown, and we highlight expression of the WhiB3 protein in response to environmental signals presentin vivo, which is consistent with a model of QS-mediated regulation (302).

(p)ppGpp Network

The (p)ppGpp response involves the enzymes guanosine tetraphosphate (ppGpp) and guanosine pentaphosphate (pppGpp). Under starvation conditions (amino acid starvation) and other types of environmental pressure, the “alarmone” molecule is produced. The (p)ppGpp network includes Rel/SpoT homolog (RSH) proteins with a nucleotidyltransferase domain, some of which display only synthetic functions, only hydrolytic functions, or both (303,304). Other proteins, such as the RelV (p)ppGpp synthase ofVibrio (305) and the RelQ (p)ppGpp synthase of Gram-positive bacteria, have an important role in the (p)ppGpp network (48). Cell processes such as replication, transcription, and translation are influenced by the (p)ppGpp network. Also, (p)ppGpp binds to RNA polymerase, which modifies the transcriptional profile and alters the translational machinery (such as rRNA and tRNA) until nutritional conditions improve (306–308). Interestingly, bacteria deficient in (p)ppGpp production usually display massive defects in persister cell formation and survival (7).

Two different (p)ppGpp-dependent (RSH proteins and amino acid starvation conditions) (309) and -independent pathways have been studied in relation to salt tolerance inE. coli (310). InE. coli, the generation of the abnormal amino acid isoaspartate, which can be repaired by isoaspartyl protein carboxyl methyltransferase (PCM), is a specific type of protein damage that is significant for bacterial survival. The relationship between unrepaired isoaspartyl protein damage and the development ofE. coli persisters through activation of the (p)ppGpp network was recently investigated (310,311). Moreover, Harms and collaborators confirmed the important role of (p)ppGpp and Lon in the development of persister cells inE. coli (312).

Several pathways are involved in the (p)ppGpp network (RSH proteins) inS. Typhimurium (313), including (i) osmoregulation of periplasmic glucan content by expression of theopgGH operon (314); (ii) enhancement of the expression of stress-dependent genes incorporating genetic material acquired by horizontal transfer (315); (iii) regulation of virulence proteins required for intracellular survival in macrophages (316); (iv) aminoglycoside resistance (317); (v) a defense mechanism against reactive nitrogen species (RNS) encountered in the host through the RNA polymerase regulatory protein DksA (318); (vi) regulated expression of the virulence elements (motility and biofilm production) from pathogenicity island 1, which is necessary to facilitate processes such as invasion and intracellular replication in host cell lines, such as human epithelial cells, as well as uptake by macrophages (319–321); and (vii) development of persister cells by inhibition of bacterial growth interfering with FtsZ assembly (322).

Several functions have been associated with the (p)ppGpp network (amino acid starvation) inV. cholerae. In 2012, a study ofV. cholerae investigated how biofilm formation is controlled by a tangled regulatory mechanism, with QS acting as a negative regulator, the restrictive response mediated by (p)ppGpp synthases (RelA, SpoT, and RelV) acting as a positive agent, and both interacting to coordinate the production of biofilm with the environmental conditions (323). Moreover, several studies have associated this system with the development of virulence elements, such as cholera toxin (CT) and toxin-coregulated pilus (TCP) (323–325). However, it has also been found that production of hemagglutinin (HA)/protease, which influences the formation of biofilm and motility inV. cholerae, is independent of the (p)ppGpp network but requires HapR, RpoS, and cyclic AMP receptor protein (CRP) (326). It was recently shown that (p)ppGpp positively controls the production of acetoin and that this specific role of (p)ppGpp inV. cholerae enables the pathogen to survive in environments with considerable concentrations of glucose, as in the human intestine (327). Finally, the (p)ppGpp network in this microorganism has been linked to RpoS, which manages the “mucosal escape response” by establishing a specific response and executing chemotaxis and motility through intracellular proteolysis (25,328).

However, the extensive literature shows that different intracellular stress responses, such as the SOS response, ROS, and (p)ppGpp (RSH proteins), can transform a subset ofK. pneumoniae cells into persister cells with antibiotic tolerance (Fig. 2) (329). In addition, ROS generation is induced by multiple factors, such as suboptimal concentrations of aminoglycosides (which also activate the SOS response), paraquat, and H₂O₂ (control by RpoS, SoxRS, and YjcC). It can thus be concluded that antimicrobial treatment can promote the persistence phenotype inK. pneumoniae (330).

H. pylori must withstand the inhospitable conditions of the human stomach and does so via a minimum number of transcriptional regulators which control the stringent response, as analyzed in different studies (331,332). Arel/spoT homolog (RSH) gene-deleted mutant was incapable of surviving under extreme conditions of acidity and oxygenation, including during infection and transmission (332). Moreover, the Rel protein has been demonstrated to be vital for the persistence phenotype inH. pylori inside macrophages during phagocytosis in the gastric environment (333). In addition, CO₂ restriction considerably raises the level of (p)ppGpp and ATP inside this bacterium, although it does not reduce the mRNA level, indicating activation of a stringent response (334).

InC. jejuni strains, the (p)ppGpp network (RSH proteins), together with the phosphohydrolases (PPX/GPPA) and polyphosphates [poly(P)], has been related to motility, biofilm production, and the ability to survive under stress conditions, such as nutrient deficiency, as well as in the process of invasion and the persistence phenotype within the host cell (335,336).

InE. faecalis, the lack of (p)ppGpp production results in a lower ability to maintain biofilm development (337). In this pathogen, (p)ppGpp production is regulated by the Rel/SpoT (RSH) proteins RelA and RelQ synthetase (338). RSH activates a strict response so that changes in (p)ppGpp levels affect survival under stress conditions as well as the virulence capacity (339). In a vancomycin-resistantEnterococcus faecium (VRE) subpopulation, a mutation in the stringent response (SR) pathway was recently reported that caused an increase in reference (p)ppGpp levels, which triggered antibiotic tolerance inside the biofilm (340). Finally, alarmone levels regulate the responses against environmental stress, tolerance to antibiotic treatment, and virulence elements inE. faecalis (341,342).

InShigella spp., with the stringent response, the RSH proteins together with the DksA protein showed activity (343).

Little is know about the role of the (p)ppGpp network in bacteria such asYersinia enterocolitica andClostridium difficile.

Persistence phenotype infections produced byS. aureus are nutrient restriction reactions that directly depend on the (p)ppGpp mechanism (344). The involvement of (p)ppGpp signaling in the development of persister cells as well as in the acquisition of antibiotic tolerance byS. aureus cells has been described (344). Nevertheless, more detailed analysis is required in relation to molecular principles, as recent studies did not find any connection between (p)ppGpp signaling and the development of persister cells inS. aureus (345,346). CodY24, a repressor, has been shown to regulate expression ofS. aureus gene homologues of Rel/SpoT proteins (RSH proteins), i.e.,rsh genes, which constitute a distinct class of (p)ppGpp synthase genes (347). Mutations incodY or inrsh were not found to have any consequences on the number of persister cells during growth (346). It has also been noted thatS. aureus has putative GTPases that are capable of recognizing guanosine tetraphosphate and guanosine pentaphosphate with a high affinity (345). Further analysis confirmed that these are active GTPases regulated by the presence of ribosomes (activation) and (p)ppGpp (inhibition). Once these molecules were characterized, it became clear that bacteria have a mechanism whereby cell growth can be halted under stress conditions by activation of (p)ppGpp, which blocks the correct formation of 70S ribosomes (345).

InP. aeruginosa strains, the RelA/SpoT protein RSH (stringent response) and the RpoS protein (stress conditions) promote the tolerance ofP. aeruginosa biofilms to ciprofloxacin but not to tobramycin (Fig. 2) (348). RSH proteins have been described for this pathogen (349). Interestingly, inAcinetobacter oliveivorans DR1, QS controls (p)ppGpp synthase (RSH proteins), AHL, and histidine kinase proteins during participation in biofilm production and hexadecane metabolism (350).

As forcis-2-dodecenoic acid factor (discovered inB. cenocepacia), it belongs to the diffusible signal family and has been associated with increased levels of RecA (SOS response) and (p)ppGpp (RSH proteins) and a reduction in biofilm formation (Fig. 2) (351).

M. tuberculosis contains homologues of Rel proteins that react to low nutrient levels via activation of (p)ppGpp (352,353). These proteins are necessary for growth in aerobic and anaerobic environments as well as for long-term survival in response to starvation (352), and they induce drug tolerance (354). In guinea pigs, cells which had lost Rel proteins were associated with a remarkable lack of tubercle lesions as well as an absence of caseous granulomas in histological sections (355). Interestingly, the success of theM. tuberculosis pathogen depends on cell growth in the host, regulated by (p)ppGpp (RSH proteins) and CarD (356). The lack of the CarD protein led to killing ofM. tuberculosis due to DNA damage, starvation, and oxidative stress, all of which led to a reduction of rRNA transcription (Fig. 2) (356).

Toxin-Antitoxin Systems

Finally, one of the best-studied mechanisms of formation of persister cells involves toxin-antitoxin (TA) systems, which trigger a state of bacterial dormancy to evade the effects of drugs or stress conditions (8). TA systems are small genetic systems located on bacterial plasmids as well as on chromosomes. TA loci usually are comprised of two genes, which encode a stable toxin and an unstable antitoxin that inhibits the toxin. TAs are currently divided into six distinct classes on the basis of the proteomic nature of the corresponding antitoxin (1,16). SeeFig. 4 for an explanation of the six best-studied types of TA modules. Critically, deletion of a single TA system that reduces persistence under certain conditions has been shown for themqsR/mqsA locus (12,357), thetisB/istR locus (181), and thedinJ/yafQ locus (358). Finally, several TA systems are triggered by the SOS system and (p)ppGpp to drive the development of persister cells (Fig. 2) (181,359).

Research on the TA modules ofEscherichia coli has provided most of the information that exists regarding persister formation (360). Also, type I, type II, and type IV TA loci are localized in the cryptic prophages ofE. coli (361). In 2011, a model ofE. coli persister formation based on the expression of 10 mRNAs for type II TA endonuclease modules was proposed (362). However, we must point out that that study was recently retracted due to the discovery of inadvertent artifacts (312). The following class II TA modules have been described: (i) the HipBA TA module, (ii) the TisB/IstR TA module, (iii) the HokB/SokB TA module, (iv) the YafQ/DinJ TA module, (v) the MazEF TA module, and (vi) the MqsRA TA module. ThehipA toxin gene was the first gene to be associated with the production of persister cells (50,363). TA loci encoding mRNases and persistence development are closely related (364,365). In addition, an increment of the expression of HipA toxin inE. coli has been reported to halt growth by boosting (p)ppGpp production via RelA, a signal commonly related to amino acid requirements (365). By use of chloramphenicol to inhibit (p)ppGpp production in HipA-arrested cells, effects such as halting the initiation of replication and RNA synthesis were reduced, thus enabling recovery of susceptibility to β-lactam antibiotics (365). The TisB/IstR TA module is activated by the SOS system. TisB works as an ion channel which reduces proton motive force and the amount of ATP, enhancing the formation of persistent cells and causing antimicrobial tolerance (180). The HokB/SokB TA module is regulated by the (p)ppGpp system (181,359). For the YafQ/DinJ TA module, the toxin shows an association with increasing persistence by reducing indole, thus establishing a relationship between the TA systems and the cell signaling QS system (224). The MazF toxin, which generally breaks down cellular RNAs, halts cell growth for some time and promotes formation of persister cells (366). The MqsR toxin influences persister cell formation (357). Moreover, the MqsRA TA inE. coli is physiologically vital for survival of bacterial cells in the gallbladder and upper intestinal tract, where concentrations of bile are generally high (367). As previously mentioned, TA systems promote persister states in bacteria by repressing bacterial metabolism or inhibiting cellular growth by the toxin. This state leads to bacterial tolerance of environmental stressors (368).

The presence ofSalmonella inside macrophages creates stress conditions for the bacterium and induces the production of a subpopulation of persister bacteria by class II TA modules (369). Fourteen putative class II TA modules have been described for this pathogen, all of which are related to the development of persister cells inside macrophages. Among these, the toxin (TacT) contributes to the formation of these persisters inSalmonella populations by transiently blocking translation (370). The TacT toxin is an acetyltransferase that inhibits translation of tRNA molecules by disrupting the primary amine group of the amino acids, also favoring the formation of persister cells by the pathogen (370).

ForV. cholerae, TA loci have been described as being present in a superintegron.V. cholerae TAs were assigned to the Phd/Doc, HigBA, RelBE, and HigBA families (371). However, only RelBE-family TA systems inV. cholerae are involved in biofilm and ROS generation (Fig. 2) (371).

Klebsiella pneumoniae isolates have a major role in antibiotic resistance, and the genes for several type I and II TA systems (Hok/Sok, PemK/PemI, and CcdA/CccB) (16) have previously been identified on resistance plasmids carried by this bacterium (372). A bioinformatics approach was used to analyze the distribution of the locus of the type II system and to determine the variability in the TA loci from 10 complete sequenced genomes ofK. pneumoniae, revealing numerous putative type II TA loci (373). Some RelBE-like TA systems were also distributed in a manner different from that for theK. pneumoniae RelBE systems (59). Thus, the distributions of RelBE_1kp and RelBE_2kp loci differ in plasmids and chromosomes, although they were found in the sameK. pneumoniae isolate (16,373). However, a detailed distribution and the implications for the development of a persistence phenotype inK. pneumoniae are unknown (373).

A new type I TA system, the AapA1/IsoA1 locus, present on the chromosome ofH. pylori, was recently characterized (374). Several type II TA systems associated with the bacterial persistence phenotype have also been localized in this pathogen, including (i) the HP0894-HP0895 proteins (375,376), (ii) the HP0892-HP0893 proteins (RelE-family TA system), and (iii) the HP0967-HP0968 proteins (Vap family) (374).

CjrA/CjpT (type I) and VirA/VirT (type II) TA systems were identified inCampylobacter spp. (377). These systems were encoded by the pVir plasmid, which is involved in virulence and natural transformation. VirT belongs to the RelE family, one of the best-studied TA systems (374,377).

Several plasmids encode toxin-antitoxin systems in strains ofEnterococcus spp., as follows: (i) the plasmid pAD1-encoded Fst toxin (type I toxin-antitoxin) inE. faecalis affects the permeability of the membrane, thus altering the cellular responses to antibiotics (378–382); and (ii) plasmids encoding vancomycin resistance and harboring genes for the ω-ε-ζ Par toxin-antitoxin and Axe-Txe toxin-antitoxin have been located, but their involvement in the presence of persister cells has not been analyzed (383–386). Moreover,mazEF,mazEG, andhigBA loci have often been found inE. faecalis andEnterococcus faecium clinical strains (387).

On the other hand, type II TA systems are related to bacterial persistence inShigella sp. isolates and include YeeUT (388,389), VapBC (390,391), GmvAT, and CcdAB (392), while the only system described forYersinia enterocolitica is the CcdA/B TA system, and its function has not been analyzed (393).

Only one type II TA system has been described forC. difficile, namely, MazEF (endoribonuclease), which is involved inC. difficile sporulation (68). However, by means of the RASTA-Bacteria TA database, additional putative TA systems, the COG2856-Xre and Fic systems, are assumed to exist in strain 630 ofC. difficile (394).

S. aureus harbors some annotated chromosomal TA systems, and their function in persister formation is of interest (395). Several type II toxin-antitoxin systems have been identified inS. aureus, including MazEF and Axe1/Twe1 as well as Axe2/Twe2, both of which are RelBE homologues. A recent study showed that the two open reading frames directly over thesigB operon region in theS. aureus genome, herein designatedmasES andmazFS, represent a TA system (396). However, further studies of the involvement of these TA systems in the development of persister cells must be performed. Although the findings of bioinformatics studies ofP. aeruginosa suggest that TA systems are abundant in the genome of this bacterium (397), the functions of these systems have not been established (16), except for the HigBA system, which downregulates virulence by the effect of the HigB toxin, which reduces the production of pyocyanin and pyochelin and surface motility (398).

The plasmid p3ABAYE is the most frequently found plasmid among the toxin-antitoxin plasmidic systems inA. baumannii. This plasmid (94 kb) probably encodes the following five TA systems: (i) RelBE; (ii) two HigBA systems, encoded in opposing directions; (iii) SplTA (DUF497/COG3514 domain proteins); and (iv) CheTA (HTH/GNAT domain proteins). These were found in a group ofA. baumannii clinical strains from Lithuanian hospitals. The HigBA and SplTA TA systems were particularly common (88.6% predominance, taking into account the 476 clinical samples). Remarkably, in 46 of theA. baumannii isolates analyzed, expression of the HigBA toxin-antitoxin system was not observed (399,400). All of these toxin-antitoxin systems were found in most clinical isolates ofA. baumannii belonging to the ECI and ECII groups worldwide. The function of SplTA was found to be associated with the persistence phenotype (399). Moreover, the AbkB/AbkA toxin-antitoxin system, also known as SplTA, was found to be encoded by the most frequent resistance plasmid ofA. baumannii, which carries an OXA24/40 β-lactamase (carbapenem resistance) gene (401). The toxin of this system has the ability to prevent translation when overexpressed inE. coli, through the scission oflpp mRNA plus the transfer of mRNA, all of which indicate that the AbkB toxin acts as an endoribonuclease. The stability of the plasmid in the absence of selection pressure can be explained by the presence of the AbkB/AbkA system, especially in the case of small plasmids pAC30a and pAC29a, which lack abla_OXA24/bla_OXA40-like gene (401). Moreover, in a recent study of isolates ofA. baumannii with resistance to carbapenem due to the presence of a plasmid encoding OXA24 β-lactamase and the AbkAB TA module, we analyzed the presence of a link between molecular mechanisms associated with the development of tolerance to a biocidal compound (chlorhexidine) and later formation of a subgroup of persister cells in the presence of an antibiotic (imipenem). These persister cells showed overexpression of theabkB toxin gene as well as downregulated expression of theabkA antitoxin gene (349).

Expression of most of the toxin genes (from TA systems) in biofilm cells ofB. cenocepacia is upregulated relative to that in planktonic cells (82,402). The high levels of expression of these bacterial toxins involve an increase in cellular survival after treatment with ciprofloxacin or tobramycin, confirming the importance of the toxins in the development of persister cells as well as the generation of antibiotic tolerance in biofilms (82,402). The FixL toxin was recently identified inBurkholderia dolosa, which belongs to theB. cepacia complex (BCC). This toxin is homologous to FixL, which forms part of the two-component FixL/FixJ system of theRhizobiales. InB. dolosa, thefixL gene acts as a general regulator of motility, biofilm formation, persistence, virulence, and intracellular invasion (45).

Finally, the genome ofM. tuberculosis, a particular persistence phenotype pathogen, has an abundance of toxin-antitoxin systems. Most of these modules have been found to be functionalin vivo in animal models, and they are involved in virulence and antibiotic tolerance (403–406). To date, numerous toxin-antitoxin systems (confirmed and putative) have been identified in the H37Rv isolate ofM. tuberculosis; the most frequent are type II TAs (VapBC, MazEF, YefM/YoeB, RelBE, HigBA, and ParDE) (Fig. 5) (404). Interestingly, no other type of TA system has been detected in this bacterium (407,408). MostM. tuberculosis systems (409) have been analyzed empirically, inMycobacterium smegmatis andE. coli, with the aim of determining the toxin function in growth restriction as well as how to neutralize this function. Thus, researchers found that 37 of the TAs were functional under at least one condition (404,405,410–413). The articles cited summarize the current knowledge of theM. tuberculosis toxin-antitoxin modules. Moreover, analysis of theM. tuberculosis persister transcriptome shows positive regulation of the toxin-antitoxin systems (213,414). Although the involvement of different TA modules in this repertoire is not fully understood, functional specialization can be considered due to the synergy observed under certain stress conditions (405,406).

We summarize the molecular mechanisms of tolerance and persistence previously described for each pathogen inTable 1.

TABLE 2.

R. Trastoy is a Clinical Microbiologist and obtained her degree in biology from the University of Santiago de Compostela (USC), Galicia, Spain (2007 to 2012), specializing in molecular biology. Since then, she has specialized in clinical microbiology and parasitology at the USC University Hospital Complex (CHUS), Galicia, Spain (2013 to 2017). During this period, she began conducting research in the field of microbiology. She is currently developing a line of research on hepatitis B virus, undertaking doctoral research within the framework of a national project. In addition, she is collaborating on different research projects, such as “Clinical Phage Therapy: New Challenges,” “Antimicrobial Persistence and/or Tolerance,” and “Molecular Diagnostic Tools: Development of Molecular Kits,” within the INIBIC-CHUAC microbiology research group, A Coruña, Spain, directed by M. Tomás. She also has some experience in clinical practice as a microbiologist.

T. Manso is currently a Ph.D. student in microbiology, in the odontologic sciences group, led by I. Tomás. She obtained her degree in chemistry from the University of Santiago de Compostela (USC), Spain, in 2013. Afterwards, she carried out training as a clinical microbiologist at the USC University Hospital Complex, completing her specialist training in May 2018. She has conducted research in microbiology from 2014 onwards. Since 2016, she has collaborated with M. Tomas on assignments related to resistance and virulence mechanisms of different pathogens. She has reviewed studies in journals, includingFrontiers.

L. Fernández-García obtained her degree in biology from Oviedo University (2007 to 2012) and her master's degree in cellular, molecular, and genetic biology from A Coruña University (2014 to 2015). She is currently undertaking Ph.D. research at the Institute for Biomedical Investigation-A Coruña University Hospital Complex (INIBIC-CHUAC) as a member of the microbiology group, under the supervision of M. Tomás. She is currently the recipient of a Xunta de Galicia Ph.D. student contract. Her Ph.D. research focuses on mechanisms of persistence and tolerance in nosocomial pathogens. She has published nine articles in scientific journals and has also published one book chapter and has another in press.

L. Blasco obtained her Ph.D. in biotechnology from the University of Santiago de Compostela (USC) in 2011. She began her research career while undertaking a master's degree program in biotechnology at the USC. She has participated as a member of the biotechnology group of the Microbiology and Parasitology Department of the USC, working on several projects within the field of industrial microbiology. Since 2015, she has been carrying out postdoctoral research as part of the microbiology group led by M. Tomás at the Institute for Biomedical Research-A Coruña University Hospital Complex (INIBIC-CHUAC), Spain. Her main research interest is the search for new treatments for use in the fight against multiresistant bacteria (bacteriophages, endolysins, and quorum sensing inhibition).

A. Ambroa is currently pursuing a Ph.D. degree at the University of A Coruña (UDC) and has been undertaking research at the Institute for Biomedical Research, A Coruña (INIBIC), Spain, since September 2017. He obtained his degree in biotechnology from the Rovira i Virgili University (Tarragona, Spain) in 2016. He has completed internships at the Pontevedra Provincial Hospital (Pontevedra, Spain; June 2015), the Sant Joan de Reus University Hospital (Reus, Spain; January to March 2016), and the Faculty of Medicine and Health Science of the Rovira i Virgili University (Reus and Tarragona, Spain; March to June 2016). In 2017, he was awarded a master's degree in clinical investigation (with a specialty in clinical microbiology) from the University of Barcelona. During the master's degree course, he also completed another internship, at the Vall d'Hebron Hospital (Barcelona, Spain; January to June 2017). He is currently investigating the role of the type VI secretion system (T6SS) in multidrug-resistant bacteria in relation to virulence and resistance mechanisms, under the supervision of M. Tomás.

M. L. Pérez del Molino obtained a Ph.D. in the area of chemical physics from the University of Santiago de Compostela (USC), Galicia, Spain, with a specialty in clinical microbiology and parasitology at the University Clinical Hospital of Santiago de Compostela (1980 to 1983). Since 2016, she has been Head of the Microbiology and Parasitology Department of the University Clinical Hospital of Santiago de Compostela. She previously worked as an Assistant Professor in the Department of Microbiology and Parasitology of the USC (1984 to 1986). Subsequently, she worked as a Clinical Microbiologist in the area of diagnosis of respiratory pathology, focusing on tuberculosis disease (1988 to 2016), and as Head of the reference laboratory of mycobacteria in Galicia (1998 to 2018). She has collaborated with the WHO on studies of resistance to antituberculosis drugs; her work features over 60 publications about microbiological diagnosis, epidemiology, and antimicrobial resistance of mycobacteria and other respiratory pathogens.

G. Bou received his Ph.D. from the Molecular Biology Center (CSIC)-Autonoma University, Madrid, Spain. He also completed a residence in clinical microbiology at the Ramon y Cajal Hospital. Afterwards, he was granted a postdoctoral position with the Fulbright Scholarship program to work in the Laboratory of Medicine at Mayo Clinic, Rochester, MN. Dr. Bou then served as an Investigator at the National Health System in Spain (2001 to 2005) and as a consultant in clinical microbiology (2005 to 2010), and at present, he is the Head of the Microbiology Department of the University Hospital A Coruña (CHUAC). Since 2009, he has been an Associate Professor of medical microbiology at the University of Santiago de Compostela. Dr. Bou's research focuses on understanding the molecular basis for antimicrobial resistance in human pathogens, developing rapid tests for detecting resistant organisms, and designing and developing bacterial vaccines. So far, he has published more than 200 international peer-reviewed papers on these topics, as well as obtaining 7 related patents. Recently, he was conferred the honorary title of ESCMID Fellow for professional excellence and service to society.

R. García-Contreras has been an Associate Professor in the Microbiology and Parasitology Department of the Medicine Faculty of the National Autonomous University of Mexico (UNAM) since 2014. From 2010 to 2014, he was an Associate Professor at the National Institute of Cardiology. In 2005, he obtained his Ph.D. at UNAM. He completed two postdoctoral positions, the first in the Department of Chemical Engineering at Texas A&M University, in the group of Thomas K. Wood, working on the genetic basis of biofilm formation inEscherichia coli, and the second in the Molecular Cell Physiology Department at the VU University of Amsterdam, with Fred Boogerd, working onE. coli central metabolism. Currently, his research is centered on the study of the resistance mechanisms ofPseudomonas aeruginosa against antivirulence compounds and novel antimicrobials, the influence of quorum sensing in virulence and bacterial physiology, and the repurposing of drugs to treat multidrug-resistant bacteria.

T. K. Wood is the Endowed Biotechnology Chair and a Professor in the Department of Chemical Engineering at Pennsylvania State University. He was formerly the Northeast Utilities Endowed Chair in Environmental Engineering at the University of Connecticut (1998 to 2005) and the O'Connor Endowed Chair at Texas A&M University (2005 to 2012). He obtained his Ph.D. in chemical engineering from North Carolina State University in 1991 by studying heterologous protein production and obtained his B.S. from the University of Kentucky in 1985. His current research pursuits include understanding the genetic basis of biofilm formation in order to prevent disease and to utilize biofilms for beneficial biotransformations, including remediation, green chemistry, and energy production. He also uses systems biology approaches to understand cell resistance, specifically discerning the roles of toxin-antitoxin systems and cryptic prophages in antibiotic resistance and persistence. He also has utilized protein engineering to control biofilm formation as well as for bioremediation and green chemistry.

M. Tomás, M.D., Ph.D. (and Clinical Microbiologist), has investigated different mechanisms of resistance to antimicrobials in nosocomial MDR pathogens in various research centers, within the framework of the Rio Hortega and Miguel Servet program (ISCIII-SERGAS). She is currently working as the Molecular Microbiology Coordinator in the Microbiology Department of CHUAC and as a Principal Investigator (PI) in the Institute for Biomedical Research (INIBIC-CHUAC), initiating new research on the relationships between resistance, tolerance, and persistence mechanisms in microbial pathogens to improve new anti-infective treatments, such as phage and antivirulence therapies against persister cells. She has over 70 publications and 3 patents related to new anti-infective treatments and molecular techniques and has completed more than 10 projects as PI (5 research projects and 5 innovation projects) (http://www.mariatomas.me/). Finally, she is Guest Editor for several international journals (Frontiers in Cellular and Infection Microbiology andMarine Drugs) and is a member of ASM, ECCMID, SEIMC, and the REIPI network.

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