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Staphylococcus aureus chronic and relapsing infections: Evidence of a role for persister cells An investigation of persister cells, their formation and their role in S. aureus disease Brian P. Conlon Staphylococcus aureus is an opportunistic pathogen capable of causing a variety of diseases including osteomyelitis, endocarditis, infections of indwelling devices and wound infections. These infections are often chronic and highly recalcitrant to antibiotic treatment. Persister cells appear to be central to this recalcitrance. A multitude of factors contribute to S. aureus virulence and high levels of treatment failure. These include its ability to colonize the skin and nares of the host, its ability to evade the host immune system and its development of resistance to a variety of antibiotics. Less understood is the phenomenon of persister cells and their role in S. aureus infections and treatment outcome. Persister cells occur as a sub-population of phenotypic variants that are tolerant to antibiotic treatment. This review examines the importance of persisters in chronic and relapsing S. aureus infections and proposes methods for their eradication.

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Keywords: antibiotics; biofilm; persister; relapse; Staphylococcus aureus; tolerance; toxin–antitoxin (TA)

DOI 10.1002/bies.201400080 Antimicrobial Discovery Center, Northeastern University, Boston, MA, USA Corresponding author: Brian P. Conlon E-mail: [email protected]

Bioessays 36: 0000–0000, ß 2014 WILEY Periodicals, Inc.

Introduction Persister cells were first identified by the Irish microbiologist, Joseph Bigger, in 1944 [1]. A culture of Staphylococcus aureus treated with penicillin resulted in the death of the vast majority of cells and the survival of a small subpopulation of “persisters” that occurred at a frequency of about 1 in 106 cells. Bigger showed that these persisters, upon regrowth, were indistinguishable from the original population. The remainder of the 20th century did little to further our understanding of persister cells, their nature or their formation. Thankfully, a revival in the field has taken place, particularly over the past decade, and much has been learned about these antibiotic evading cells. There is an increasing body of work supporting the role of persister cells in chronic and relapsing disease. Using Escherichia coli as a model organism persisters are described as non-growing, dormant, phenotypic variants of regular cells with high tolerance for antimicrobial treatment [2]. In E. coli, toxin–antitoxin (TA) systems have been heavily implicated in persister formation. The hipBA TA locus is the best studied example of this. The hipA gene encodes the toxic protein HipA, which is neutralized by the HipB antitoxin. The Lon protease can degrade HipB, allowing HipA to cause cellular shutdown and persister formation [3]. It was recently shown that HipA is a kinase that phosphorylates an aminoacyl-tRNA synthetase, which halts protein synthesis [4]. There are also 11 TA mRNA interferases in E. coli K12 [5]. Although overexpression of the endonucleases demonstrated growth inhibition and persister formation, single deletions of any individual TA locus failed to impact persister formation. This suggested redundancy in the system. Maisonneuve et al. serially deleted these TA loci and found that deletion of five TAs resulted in a significant decrease in persister cells. A further reduction was observed for each progressive deletion and the D10 strain displayed a www.bioessays-journal.com

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100-fold reduction in persister formation [5]. Toxin–antitoxin systems have recently been shown to mediate persister formation of Salmonella [6]. Helaine et al. [6] showed that Salmonella persister formation, in vivo, relies on TA modules and is induced by internalization by macrophages during infection. Toxin–antitoxin loci are widespread in bacterial genomes [7]. Whether or not their role in persister formation is highly conserved remains unknown, the majority of efforts being focused on E. coli persisters. Knowledge of the role of TA loci in Gram-positives is particularly limited, and new TA loci are continuing to be identified and annotated, as recently illustrated in a study of TA systems of S. pneumoniae [8]. S. aureus harbors three annotated, chromosomal toxinantitoxin systems, and it will be interesting to investigate their role in persister formation [9]. The role of TA modules in persister formation in E. coli has been linked to (p)ppGpp and the stringent response [10]. The stringent response is a highly conserved stress response [11]. Under amino acid starvation, along with a variety of other stress conditions, (p)ppGpp accumulates in the cell and can result in shutting down of replication, transcription and translation [12–15]. Maisonneuve et al. [10] showed that stochastic switching to slow growth and persister formation is governed by (p)ppGpp activating TA loci. A separate study by Amato et al. found a similar connection, where changing of the nutrient environment induced persister formation through the stringent response [16]. This group also demonstrated that a similar mechanism of persister formation occurs in an E. coli biofilm population [17]. Similar findings were reported in a study on Pseudomonas aeruginosa persisters [18]. The stringent response is increasingly associated with persister formation although its involvement in persister formation in Gram-positive organisms, including S. aureus, remains to be seen. Implicating persisters directly in disease is of utmost importance. As mentioned, Helaine et al. [6] showed that TA-dependent persister formation of Salmonella occurs in vivo, and is induced in macrophages. P. aeruginosa persisters have also been directly linked to disease. P. aeruginosa is an important opportunistic human pathogen, and causes a variety of infections including pneumonia and septic shock. Although an infection with P. aeruginosa is usually acute, it can also cause chronic and recurrent infection in the lung of cystic fibrosis patients [19]. Mulcahy et al. [20] showed that early isolates taken from a cystic fibrosis lung produced significantly less persisters than late isolates present after repetitive rounds of antibiotic therapy. Also, persister levels of longitudinal isolates from a single cystic fibrosis patient showed a progressive increase in persister levels, culminating in a 100-fold increase in persister formation observed in the final four isolates tested. These findings strongly implicate persister formation in the recalcitrance of P. aeruginosa to antibiotic therapy in cystic fibrosis patients [20]. Similar characterization of longitudinal S. aureus isolates from chronic infections may provide evidence of the importance of persisters in S. aureus infection. Also, once a better understanding of S. aureus persister formation is acquired, fluorescence based systems will allow us to detect them in vivo.

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Staphylococcus aureus is highly tolerant to antibiotic treatment S. aureus produces persister cells similarly to other bacteria – a striking increase in persisters occurring as cells transition to the stationary phase [21]. At this point the entire stationary phase population demonstrates full tolerance to a variety of antibiotics [21]. This is in contrast with E. coli where 90% of the cells remain susceptible to killing by fluoroquinolones or aminoglycosides [21]. Stationary phase S. aureus has the capacity to survive long-term incubation with 10-fold the minimum inhibitory concentration (MIC) of a variety of bactericidal antibiotics [22]. Indeed, it appears that stationary phase populations are more recalcitrant to antimicrobial treatment than biofilm populations [22]. A subpopulation of cells within the biofilm may be in a similar state to those in stationary phase, and hence survive antibiotic treatment. The mechanism by which S. aureus adjusts to its environment to reach this antibiotic tolerant state is, as yet, poorly understood. It appears that the ClpP protease plays a role in persister formation because mutation of clpP leads to increased susceptibility of S. aureus to killing by rifampicin and ciprofloxacin [22]. The precise role of the ClpP protease remains to be seen. That these persister cells are highly tolerant to antibiotics and occur at high frequency under growth limiting conditions and biofilm, strongly suggests that they play a role in S. aureus infection.

Antibiotic tolerance of biofilm is due to persister cells S. aureus is a biofilm producing microorganism. A biofilm can be defined as a population of bacteria attached to a surface and embedded in an exopolymeric matrix. Biofilms have been heavily implicated in a variety of S. aureus diseases such as osteomyelitis, periodontitis, endocarditis, chronic wound infection and infection of indwelling medical devices [23– 27]. S. aureus biofilm can consist of a variety of protein adhesins, exopolysaccharides, extracellular DNA or any combination of these [28]. The redundancy apparent in biofilm formation underpins the importance of the process in the life cycle of S. aureus. Biofilm-negative strains of S. aureus have been shown to be unable to produce infection in a variety of animal models [29, 30]. Biofilms are a protective environment. They protect cells from complement immunity and phagocytosis [31–33], and biofilms were seen to be extremely tolerant to antibiotic treatment [34]. It was originally hypothesized that biofilms protect indwelling cells from antibiotic penetration [35]. However, this was shown to be largely incorrect, because antibiotics penetrate biofilms quite well [36–39]. It was finally shown that the antibiotic tolerance of biofilms could easily be explained by persister cells. Although eradication of biofilms with bactericidal antibiotics is extremely difficult, so too is eradication of a stationary phase, planktonic culture [21]. A model for relapsing biofilm infection was proposed by Kim Lewis [40]. It was proposed that a bactericidal antibiotic will kill the Bioessays 36: 0000–0000, ß 2014 WILEY Periodicals, Inc.

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majority of cells in a biofilm, but that persisters will survive. These persisters are shielded from the immune system by the biofilm matrix. Once antibiotic treatment is ceased, these persisters can resuscitate and revert to a growing state and repopulate the biofilm, causing a relapse of infection (Fig. 1). The relatively high numbers of persisters in the biofilm may be related to the altered metabolism and gene expression that have been previously well characterized [41, 42]. The mechanism of resuscitation of persisters within the biofilm, once antibiotic is removed, remains a poorly understood process. The ability of S. aureus to form abundant biofilms, coupled with its tolerance to antibiotics when in a non-growing state, can explain the difficulty in treating a variety of S. aureus infections and the intensive and long-term antibiotic therapy often required to eradicate infection.

S. aureus persisters are an important aspect of antibiotic treatment failure To further substantiate a role for persisters in S. aureus infection, we must examine treatment failure and relapse, and the relative roles of other factors such as antibiotic resistance development and antibiotic penetration to infected sites. S. aureus infection is often divided into two groups, MSSA (methicillin sensitive S. aureus) and MRSA (methicillin resistant S. aureus). The classification distinction is based on resistance to beta-lactam antibiotics that primarily results from the presence of the mecA gene, coding for PBP2A, a Bioessays 36: 0000–0000, ß 2014 WILEY Periodicals, Inc.

penicillin binding protein with very low affinity for betalactam antibiotics [43]. A common conception is that disease outcome is primarily influenced by antibiotic resistance; hence MRSA attracts the majority of attention. Undoubtedly the emergence of methicillin resistance in 1961 was a hugely significant occurrence, and its subsequent spread has greatly influenced how S. aureus infection is treated [44]. Beta-lactams have many exceptional properties that made them a particularly desirable treatment option. They’re broadspectrum, particularly non-toxic, orally available, and relatively low-cost. Also, many MRSA have become multi drug resistant further complicating treatment options [45]. However, treatment failure is a more complex issue and cannot be explained by resistance development alone. MSSA strains remain to be problematic and difficult to treat and treatment failure remains common. Furthermore, antibiotics such as vancomycin, linezolid, and daptomycin are active against MRSA, and resistance development to these drugs is confined to rare and isolated events [46–48]. Nonetheless treatment failure with these antibiotics, without the development of resistance remains a major healthcare problem [49, 50]. Relapse of bacteremia following vancomycin treatment was shown to be independent of vancomycin resistance development, which is exceptionally rare [51]. Likewise, studies demonstrate linezolid treatment failure and relapse of infection, independent of resistance to linezolid [52, 53]. Together these data suggest that although S. aureus antibiotic resistance is a major cause for concern, antibiotic treatment failure is a more complex multi-faceted issue than can be explained by resistance alone. Antibiotic penetration to the site of infection is required in order to eradicate a bacterial population. It is reasonable to conclude that poor penetration to certain sites of the body could lead to the survival of a small population of bacteria that will cause relapse of infection after therapy is ceased. However, numerous studies have shown that most antibiotics can penetrate quite well, even into bone tissue in the case of osteomyelitis treatment [54–56]. The penetration to particular tissues is specific to each antibiotic and is an important property. Nonetheless, research findings indicate that treatment failure cannot be solely explained by a lack of antibiotic penetration.

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Figure 1. Model of relapsing biofilm infection. S. aureus cells first attach to a surface before proliferation and matrix production form the biofilm. The host immune system kills regular cells (red) and persisters (blue) in the planktonic state, but cannot access cells within the biofilm matrix. Antibiotics penetrate the matrix, killing the majority of cells but leaving behind biofilm-associated persisters. Once antibiotic treatment ceases these persisters resuscitate and grow resulting in relapse of infection.

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Figure 2. Killing a persister cell. Activity of a conventional antibiotic against an actively growing cell (red) and a dormant persister (blue). The efficacy of the antibiotic is dependent on the activity of a cellular process that can be down-regulated or switched off in a persister cell. An ideal persister antibiotic will activate the target system and corrupt it, resulting in death of the cell.

Persister cells, residing in a biofilm, surviving long-term antibiotic treatment can help explain the high rates of treatment failure and relapse of infection associated with S. aureus. This cannot be adequately explained by resistance development or poor antibiotic penetration alone. The first evidence of S. aureus persisters in vivo can be seen in a deep-seated thigh wound model of infection [22]. A single day of vancomycin treatment resulted in the killing of around 99% of MRSA cells in the mouse thigh. A further day of vancomycin treatment did not result in any further decline in colony forming units (cfu), suggesting a tolerant persister subpopulation. Microscopy revealed the infection to be a biofilm, perfectly fitting the biofilm-persister model of relapsing infection [22]. This study also revealed an important finding regarding persister cells: Despite their tolerance to conventional antibiotics, they can be killed by the corruption of the ClpP protease leading to eradication of infection [22].

Eradication of persisters and treatment of chronic infection Persister have been described as dormant cells [57]. Although the use of the word “dormant” is not without controversy, it is widely accepted that persisters are non-growing and display a reduction in cellular activity [10, 58, 59]. Conventional bactericidal antibiotics target active processes in the cell. The corruption of these active processes leads to cell death. For example, aminoglycosides target the ribosome, corrupting protein synthesis and causing the generation of misfolded proteins, which lead to a loss of membrane integrity [60]. Betalactams target the penicillin binding proteins (PBPs) and inhibit transpeptidation during peptidoglycan biosynthesis in growing cells, resulting in cell lysis [61], and the quinolones target gyrase and topoisomerase during DNA replication, resulting in the formation of double-strand breaks [62].

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In a dormant persister cell, the processes of protein synthesis, cell division and DNA replication may be switched off or highly down-regulated. The persister cell survives antibiotic treatment. Daptomycin is a lipopeptide antibiotic that, unlike the aforementioned antibiotics, does not require an active mechanism to cause cell death. It aggregates in the bacterial membrane, causing rapid depolarization [63]. Because of this unique mechanism of action, daptomycin retains activity against non-growing, dormant S. aureus [64]. However, despite its impressive activity, a subpopulation survives treatment, even at extremely high-antibiotic concentrations [64] – though the mechanism of this tolerance remains unclear. Allison et al. [65] proposed a mechanism of persister eradication by aminoglycosides based on metabolite stimuli. They showed that specific sugars induced the uptake of gentamicin via generation of a proton-motive force, resulting in death of the persister cell. This is an extremely interesting finding, although the death of the cell is still dependent on active protein synthesis, and relies on susceptibility to aminoglycosides, to which many S. aureus strains are resistant [66]. A possible approach to targeting and killing persisters would be the activation of an antibiotic target in the persister cell and its subsequent corruption (Fig. 2). Recently, it was shown that a particular antibiotic, ADEP4, was capable of achieving this feat [22]. ADEP4 is a synthetic acyldepsipeptides antibiotic that binds the ClpP protease and results in dysregulation of proteolysis [67]. Importantly, this dysregulated proteolysis is independent of ATP [68], which may be at extremely low levels in persister cells [59]. Incubation of the highly antibiotic-tolerant stationary phase population of S. aureus with 10-fold the MIC of ADEP4 for 24 hours, resulted in massive protein degradation [22]. Killing experiments confirmed ADEP4 activity against S. aureus persisters. Activation and corruption of the ClpP protease was forcing self-digestion of persister cells. There is a high frequency of resistance due to null mutation of clpP [67]. However, it was found that mutation of clpP resulted in an increased susceptibility to conventional antibiotics, rifampicin, linezolid, and ciprofloxacin. Combining ADEP4 with rifampicin resulted in complete eradication of the population to the limit of detection in a variety of experiments [22]. Biofilm was also eradicated by this novel antibiotic combination. Importantly a deep-seated S. aureus thigh infection, recalcitrant to vancomycin therapy, was eradicated with a single day treatment with ADEP4 and rifampicin [22]. Bioessays 36: 0000–0000, ß 2014 WILEY Periodicals, Inc.

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Conclusions and outlook Persisters are increasingly linked with chronic and relapsing infection associated with numerous pathogens [6, 20, 22]. S. aureus stationary phase cells behave as persisters, exhibiting very high tolerance to bactericidal antibiotics [21, 22]. S. aureus is an avid biofilm former, and it is the causative organism of numerous chronic and relapsing infections. For these reasons, it appears that persister cells may not only play a role in S. aureus infection but that S. aureus may be the ideal model for the investigation of these drug tolerant cells and their role in disease. The mechanism of persister formation in S. aureus remains poorly understood. It is clear that upon reaching a nongrowing state, S. aureus has the capacity to reach a level of antibiotic tolerance not seen in well-characterized Gramnegatives such as E. coli or P. aeruginosa [21]. The reason for this tolerance is as yet unknown. It remains to be seen if all Gram-positive organisms exhibit similar stationary phase tolerance. Environmental cues inducing S. aureus persister formation also need to be investigated. It is possible that higher levels of persisters are induced in certain infections, hence making them more difficult to treat. Finally, the future treatment of chronic S. aureus infections remains of the upmost importance, and antibiotic tolerance and persister formation must be considered. Although susceptibility and resistance to antibiotics are the preoccupation in the clinic, it is clear that relapsing S. aureus infections regularly occur independently of any resistance development. It is proposed that treatment failure is as a result of persister cells surviving antibiotic treatment in vivo. To address this issue, antibiotics that kill persisters, and can Bioessays 36: 0000–0000, ß 2014 WILEY Periodicals, Inc.

eradicate entire bacterial populations, need to be developed. Eradication of an entire population will also reduce the likelihood of resistance development during prolonged antibiotic treatments [70, 71]. Targeting persisters by energy-independent activation and corruption of targets is an attractive future direction – as illustrated by ADEP4 activity. The development of ADEPs and the identification of other antipersister compounds can contribute to our ability to treat and eliminate chronic infection.

Acknowledgments I would like to thank Professor Kim Lewis for stimulating discussions and continued advice and support. I am grateful to Dr. Sarah Rowe for helpful and critical comments on earlier versions of this paper.

References 1. Bigger J. 1944. Treatment of staphylococcal infections with penicillin by intermittent sterilisation. Lancet 244: 497–500. 2. Balaban NQ, Merrin J, Chait R, Kowalik L, et al. 2004. Bacterial persistence as a phenotypic switch. Science 305: 1622–5. 3. Hansen S, Vulic M, Min J, Yen TJ, et al. 2012. Regulation of the Escherichia coli HipBA toxin-antitoxin system by proteolysis. PLoS One 7: e39185. 4. Germain E, Castro-Roa D, Zenkin N, Gerdes K. 2013. Molecular mechanism of bacterial persistence by HipA. Mol Cell 52: 248–54. 5. Maisonneuve E, Shakespeare LJ, Jorgensen MG, Gerdes K. 2011. Bacterial persistence by RNA endonucleases. Proc Natl Acad Sci USA 108: 13206–11. 6. Helaine S, Cheverton AM, Watson KG, Faure LM, et al. 2014. Internalization of Salmonella by macrophages induces formation of nonreplicating persisters. Science 343: 204–8. 7. Sevin EW, Barloy-Hubler F. 2007. RASTA-Bacteria: a web-based tool for identifying toxin-antitoxin loci in prokaryotes. Genome Biol 8: R155. 8. Chan WT, Moreno-Cordoba I, Yeo CC, Espinosa M. 2012. Toxinantitoxin genes of the Gram-positive pathogen Streptococcus pneumoniae: so few and yet so many. Microbiol Mol Biol Rev 76: 773–91. 9. Donegan NP, Thompson ET, Fu Z, Cheung AL. 2010. Proteolytic regulation of toxin-antitoxin systems by ClpPC in Staphylococcus aureus. J Bacteriol 192: 1416–22. 10. Maisonneuve E, Castro-Camargo M, Gerdes K. 2013. (p)ppGpp controls bacterial persistence by stochastic induction of toxin-antitoxin activity. Cell 154: 1140–50. 11. Potrykus K, Cashel M. 2008. (p)ppGpp: still magical? Annu Rev Microbiol 62: 35–51. 12. Hou Z, Cashel M, Fromm HJ, Honzatko RB. 1999. Effectors of the stringent response target the active site of Escherichia coli adenylosuccinate synthetase. J Biol Chem 274: 17505–10. 13. Artsimovitch I, Patlan V, Sekine S, Vassylyeva MN, et al. 2004. Structural basis for transcription regulation by alarmone ppGpp. Cell 117: 299–310. 14. Milon P, Tischenko E, Tomsic J, Caserta E, et al. 2006. The nucleotidebinding site of bacterial translation initiation factor 2 (IF2) as a metabolic sensor. Proc Natl Acad Sci USA 103: 13962–7. 15. Wang JD, Sanders GM, Grossman AD. 2007. Nutritional control of elongation of DNA replication by (p)ppGpp. Cell 128: 865–75. 16. Amato SM, Orman MA, Brynildsen MP. 2013. Metabolic control of persister formation in Escherchia coli. Mol. Cell 50: 475–87. 17. Amato SM, Brynildsen MP. 2014. Nutrient transitions are a source of persisters in Escherichia coli biofilms. PLoS One 9: e93110. 18. Nguyen D, Joshi-Datar A, Lepine F, Bauerle E, et al. 2011. Active starvation responses mediate antibiotic tolerance in biofilms and nutrientlimited bacteria. Science 334: 982–6. 19. Hoiby N, Koch C. 1990. Cystic fibrosis. 1. Pseudomonas aeruginosa infection in cystic fibrosis and its management. Thorax 45: 881–4. 20. Mulcahy LR, Burns JL, Lory S, Lewis K. 2010. Emergence of Pseudomonas aeruginosa strains producing high levels of persister cells in patients with cystic fibrosis. J Bacteriol 192: 6191–9.

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This study demonstrated a method for killing persisters, and showed that an antibiotic that kills persisters can eradicate biofilm and deep-seated infection. This provides the clearest evidence yet for the importance of persisters in S. aureus infection, while also proposing a mechanism for their eradication [22]. A persister cell that survives antimicrobial treatment must resuscitate to reestablish infection. Elucidating the precise metabolic, transcriptional and translational events that occur during this process would be extremely valuable. Understanding these events may allow us to induce resuscitation of persisters, rendering them susceptible to antibiotic treatment. Little is known about resuscitation of persisters of any organism. Studying persisters is often a difficult process because of the small proportion of persisters in a population, and the difficulty in identifying and isolating them [57]. S. aureus stationary phase cells behave similarly to a population of persisters, displaying high levels of tolerance to a range of antibiotics. This provides us with the ideal model to study resuscitation, and examine the chain of events that occurs as a cell moves from a tolerant dormant state to an active antibiotic susceptible state. One recent study describes the resuscitation of stationary phase S. aureus by spent culture supernatant, although much remains to be done to identify the precise factors involved [69].

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21. Keren I, Kaldalu N, Spoering A, Wang Y, et al. 2004. Persister cells and tolerance to antimicrobials. FEMS Microbiol Lett 230: 13–8. 22. Conlon BP, Nakayasu ES, Fleck LE, LaFleur MD, et al. 2013. Activated ClpP kills persisters and eradicates a chronic biofilm infection. Nature 503: 365–70. 23. Ziran BH. 2007. Osteomyelitis. J Traum 62: S59–60. 24. Baldoni D, Haschke M, Rajacic Z, Zimmerli W, et al. 2009. Linezolid alone or combined with rifampin against methicillin-resistant Staphylococcus aureus in experimental foreign-body infection. Antimicrob Agents Chemother 53: 1142–8. 25. Cuesta AI, Jewtuchowicz V, Brusca MI, Nastri ML, et al. 2010. Prevalence of Staphylococcus spp and Candida spp in the oral cavity and periodontal pockets of periodontal disease patients. Acta Odontol Latinoam 23: 20–6. 26. Petti CA, Fowler VG, Jr. 2003. Staphylococcus aureus bacteremia and endocarditis. Cardiol Clin 21: 219–33, vii. 27. Davis SC, Ricotti C, Cazzaniga A, Welsh E, et al. 2008. Microscopic and physiologic evidence for biofilm-associated wound colonization in vivo. Wound Repair Regen 16: 23–9. 28. Otto M. 2008. Staphylococcal biofilms. Curr Top Microbiol Immunol 322: 207–28. 29. Cucarella C, Solano C, Valle J, Amorena B, et al. 2001. Bap, a Staphylococcus aureus surface protein involved in biofilm formation. J Bacteriol 183: 2888–96. 30. Kropec A, Maira-Litran T, Jefferson KK, Grout M, et al. 2005. Poly-Nacetylglucosamine production in Staphylococcus aureus is essential for virulence in murine models of systemic infection. Infect Immun 73: 6868–76. 31. Domenech M, Ramos-Sevillano E, Garcia E, Moscoso M, et al. 2013. Biofilm formation avoids complement immunity and phagocytosis of Streptococcus pneumoniae. Infect Immun 81: 2606–15. 32. Schommer NN, Christner M, Hentschke M, Ruckdeschel K, et al. 2011. Staphylococcus epidermidis uses distinct mechanisms of biofilm formation to interfere with phagocytosis and activation of mouse macrophage-like cells 774A.1. Infect Immun 79: 2267–76. 33. Thurlow LR, Hanke ML, Fritz T, Angle A, et al. 2011. Staphylococcus aureus biofilms prevent macrophage phagocytosis and attenuate inflammation in vivo. J Immunol 186: 6585–96. 34. Costerton JW, Cheng KJ, Geesey GG, Ladd TI, et al. 1987. Bacterial biofilms in nature and disease. Annu Rev Microbiol 41: 435–64. 35. Gristina AG, Hobgood CD, Webb LX, Myrvik QN. 1987. Adhesive colonization of biomaterials and antibiotic resistance. Biomaterials 8: 423–6. 36. Vrany JD, Stewart PS, Suci PA. 1997. Comparison of recalcitrance to ciprofloxacin and levofloxacin exhibited by Pseudomonas aeruginosa bofilms displaying rapid-transport characteristics. Antimicrob Agents Chemother 41: 1352–8. 37. Anderl JN, Franklin MJ, Stewart PS. 2000. Role of antibiotic penetration limitation in Klebsiella pneumoniae biofilm resistance to ampicillin and ciprofloxacin. Antimicrob Agents Chemother 44: 1818–24. 38. Darouiche RO, Dhir A, Miller AJ, Landon GC, et al. 1994. Vancomycin penetration into biofilm covering infected prostheses and effect on bacteria. J Infect Dis 170: 720–3. 39. Jefferson KK, Goldmann DA, Pier GB. 2005. Use of confocal microscopy to analyze the rate of vancomycin penetration through Staphylococcus aureus biofilms. Antimicrob Agents Chemother 49: 2467–73. 40. Lewis K. 2001. Riddle of biofilm resistance. Antimicrob Agents Chemother 45: 999–1007. 41. Resch A, Leicht S, Saric M, Pasztor L, et al. 2006. Comparative proteome analysis of Staphylococcus aureus biofilm and planktonic cells and correlation with transcriptome profiling. Proteomics 6: 1867–77. 42. Resch A, Rosenstein R, Nerz C, Gotz F. 2005. Differential gene expression profiling of Staphylococcus aureus cultivated under biofilm and planktonic conditions. Appl Environ Microbiol 71: 2663–76. 43. Georgopapadakou NH, Smith SA, Bonner DP. 1982. Penicillin-binding proteins in a Staphylococcus aureus strain resistant to specific betalactam antibiotics. Antimicrob Agents Chemother 22: 172–5. 44. Jevons M. 1961. Calbenin-resistant staphylococci. BMJ 1: 124–5. 45. Shorr AF. 2007. Epidemiology of staphylococcal resistance. Clin Infect Dis 45: S171–6. 46. Bozdogan B, Appelbaum PC. 2004. Oxazolidinones: activity, mode of action, and mechanism of resistance. Int J Antimicrob Agents 23: 113–9.

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47. Boucher HW, Sakoulas G. 2007. Perspectives on Daptomycin resistance, with emphasis on resistance in Staphylococcus aureus. Clin Infect Dis 45: 601–8. 48. Sievert DM, Rudrik JT, Patel JB, McDonald LC, et al. 2008. Vancomycin-resistant Staphylococcus aureus in the United States, 2002–2006. Clin Infect Dis 46: 668–74. 49. Shields RK, Clancy CJ, Minces LR, Kwak EJ, et al. 2012. Staphylococcus aureus infections in the early period after lung transplantation: epidemiology, risk factors, and outcomes. J Heart Lung Transplant 31: 1199–206. 50. Senneville E, Joulie D, Legout L, Valette M, et al. 2011. Outcome and predictors of treatment failure in total hip/knee prosthetic joint infections due to Staphylococcus aureus. Clin Infect Dis 53: 334–40. 51. Welsh KJ, Skrobarcek KA, Abbott AN, Lewis CT, et al. 2011. Predictors of relapse of methicillin-resistant Staphylococcus aureus bacteremia after treatment with vancomycin. J Clin Microbiol 49: 3669–72. 52. Corne P, Marchandin H, Macia JC, Jonquet O. 2005. Treatment failure of methicillin-resistant Staphylococcus aureus endocarditis with linezolid. Scand J Infect Dis 37: 946–9. 53. Ruiz ME, Guerrero IC, Tuazon CU. 2002. Endocarditis caused by methicillin-resistant Staphylococcus aureus: treatment failure with linezolid. Clin Infect Dis 35: 1018–20. 54. Darley ES, MacGowan AP. 2004. Antibiotic treatment of gram-positive bone and joint infections. J Antimicrob Chemother 53: 928–35. 55. Kutscha-Lissberg F, Hebler U, Muhr G, Koller M. 2003. Linezolid penetration into bone and joint tissues infected with methicillin-resistant staphylococci. Antimicrob Agents Chemother 47: 3964–6. 56. Graziani AL, Lawson LA, Gibson GA, Steinberg MA, et al. 1988. Vancomycin concentrations in infected and noninfected human bone. Antimicrob Agents Chemother 32: 1320–2. 57. Lewis K. 2010. Persister cells. Annu Rev Microbiol 64: 357–72. 58. Kaspy I, Rotem E, Weiss N, Ronin I, et al. 2013. HipA-mediated antibiotic persistence via phosphorylation of the glutamyl-tRNA-synthetase. Nat Commun 4: 3001. 59. Dorr T, Vulic M, Lewis K. 2010. Ciprofloxacin causes persister formation by inducing the TisB toxin in Escherichia coli. PLoS Biol 8: E1000317. 60. Davis BD. 1987. Mechanism of bactericidal action of aminoglycosides. Microbiol Rev 51: 341–50. 61. Tipper DJ, Strominger JL. 1965. Mechanism of action of penicillins: a proposal based on their structural similarity to acyl-D-alanyl-D-alanine. Proc Natl Acad Sci USA 54: 1133–41. 62. Drlica K, Zhao X. 1997. DNA gyrase, topoisomerase IV, and the 4quinolones. Microbiol Mol Biol Rev 61: 377–92. 63. Steenbergen JN, Alder J, Thorne GM, Tally FP. 2005. Daptomycin: a lipopeptide antibiotic for the treatment of serious Gram-positive infections. J Antimicrob Chemother 55: 283–8. 64. Mascio CT, Alder JD, Silverman JA. 2007. Bactericidal action of daptomycin against stationary-phase and nondividing Staphylococcus aureus cells. Antimicrob Agents Chemother 51: 4255–60. 65. Allison KR, Brynildsen MP, Collins JJ. 2011. Metabolite-enabled eradication of bacterial persisters by aminoglycosides. Nature 473: 216–20. 66. Schmitz FJ, Fluit AC, Gondolf M, Beyrau R, et al. 1999. The prevalence of aminoglycoside resistance and corresponding resistance genes in clinical isolates of staphylococci from 19 European hospitals. J Antimicrob Chemother 43: 253–9. 67. Brotz-Oesterhelt H, Beyer D, Kroll HP, Endermann R, et al. 2005. Dysregulation of bacterial proteolytic machinery by a new class of antibiotics. Nat Med 11: 1082–7. 68. Kirstein J, Hoffmann A, Lilie H, Schmidt R, et al. 2009. The antibiotic ADEP reprogrammes ClpP, switching it from a regulated to an uncontrolled protease. EMBO Mol Med 1: 37–49. 69. Pascoe B, Dams L, Wilkinson TS, Harris LG, et al. 2014. Dormant cells of Staphylococcus aureus are resuscitated by spent culture supernatant. PLoS One 9: E85998. 70. Mwangi MM, Wu SW, Zhou Y, Sieradzki K, et al. 2007. Tracking the in vivo evolution of multidrug resistance in Staphylococcus aureus by whole-genome sequencing. Proc Natl Acad Sci USA 104: 9451–6. 71. Howden BP, McEvoy CR, Allen DL, Chua K, et al. 2011. Evolution of multidrug resistance during Staphylococcus aureus infection involves mutation of the essential two component regulator WalKR. PLoS Pathog 7: E1002359.

Bioessays 36: 0000–0000, ß 2014 WILEY Periodicals, Inc.

Staphylococcus aureus chronic and relapsing infections: Evidence of a role for persister cells: An investigation of persister cells, their formation and their role in S. aureus disease.

Staphylococcus aureus is an opportunistic pathogen capable of causing a variety of diseases including osteomyelitis, endocarditis, infections of indwe...
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