J. Bigger, Treatment of staphylococcal infections with penicillin by intermittent sterilisation, Lancet, vol.244, pp.497-500, 1944.

A. Brauner, Distinguishing between resistance, tolerance and persistence to antibiotic treatment, Nat. Rev. Microbiol, vol.14, pp.320-330, 2016.

N. Q. Balaban, Bacterial persistence as a phenotypic switch, Science, vol.305, pp.1622-1625, 2004.

M. Fauvart, V. N. De-groote, and J. Michiels, Role of persister cells in chronic infections: clinical relevance and perspectives on anti-persister therapies, J. Med. Microbiol, vol.60, pp.699-709, 2011.

M. S. Svenningsen, Birth and resuscitation of (p)ppGpp induced antibiotic tolerant persister cells, Sci. Rep, vol.9, p.6056, 2019.

A. Harms, Prophages and growth dynamics confound experimental results with antibiotic-tolerant persister cells, vol.8, pp.1964-1981, 2017.

C. C. Dawson, C. Intapa, and M. A. Jabra-rizk, Persisters": survival at the cellular level, PLoS Pathog, vol.7, p.1002121, 2011.

R. A. Fisher, B. Gollan, and S. Helaine, Persistent bacterial infections and persister cells, Nat. Rev. Microbiol, vol.15, pp.453-464, 2017.

T. K. Wood, S. J. Knabel, and B. W. Kwan, Bacterial persister cell formation and dormancy, Appl. Environ. Microbiol, vol.79, pp.7116-7121, 2013.

L. R. Mulcahy, Emergence of Pseudomonas aeruginosa strains producing high levels of persister cells in patients with cystic fibrosis, J. Bacteriol, vol.192, pp.6191-6199, 2010.

B. P. Conlon, 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, Bioessays, vol.36, pp.991-996, 2014.

N. Dhar and J. D. Mckinney, Mycobacterium tuberculosis persistence mutants identified by screening in isoniazid-treated mice, Proc. Natl Acad. Sci. USA, vol.107, pp.12275-12280, 2010.

L. W. Goneau, Selective target inactivation rather than global metabolic dormancy causes antibiotic tolerance in uropathogens, Antimicrob. Agents Chemother, vol.58, pp.2089-2097, 2014.

S. Helaine, Internalization of Salmonella by macrophages induces formation of nonreplicating persisters, Science, vol.343, pp.204-208, 2014.

K. N. Adams, Drug tolerance in replicating mycobacteria mediated by a macrophage-induced efflux mechanism, Cell, vol.145, pp.39-53, 2011.

C. Garzoni and W. L. Kelley, Return of the Trojan horse: intracellular phenotype switching and immune evasion by Staphylococcus aureus, EMBO Mol. Med, vol.3, pp.115-117, 2011.

F. Peyrusson, P. M. Tulkens, and F. Van-bambeke, Cellular pharmacokinetics and intracellular activity of gepotidacin against Staphylococcus aureus isolates with different resistance phenotypes in models of cultured phagocytic cells, Antimicrob. Agents Chemother, vol.62, pp.2245-2262, 2018.

J. Roostalu, Cell division in Escherichia coli cultures monitored at single cell resolution, BMC Microbiol, vol.8, p.68, 2008.

S. Helaine, Dynamics of intracellular bacterial replication at the single cell level, Proc. Natl Acad. Sci. USA, vol.107, pp.3746-3751, 2010.

G. Rollin, Intracellular survival of Staphylococcus aureus in endothelial cells: a matter of growth or persistence, Front. Microbiol, vol.8, p.1354, 2017.

J. Horn, Inside job: Staphylococcus aureus host-pathogen interactions, Int. J. Med. Microbiol, vol.308, pp.607-624, 2018.

J. Jubrail, Inability to sustain intraphagolysosomal killing of Staphylococcus aureus predisposes to bacterial persistence in macrophages, Cell Microbiol, vol.18, pp.80-96, 2016.

, Staphylococcus aureus subsp. aureus NCTC 8325, complete genome, 2014.

T. Geiger, The stringent response of Staphylococcus aureus and its impact on survival after phagocytosis through the induction of intracellular PSMs expression, PLoS Pathog, vol.8, p.1003016, 2012.

S. M. Amato and M. P. Brynildsen, Persister heterogeneity arising from a single metabolic stress, Curr. Biol, vol.25, pp.2090-2098, 2015.

F. Goormaghtigh, Reassessing the role of type II toxin-antitoxin systems in formation of Escherichia coli type II persister cells, vol.9, pp.640-658, 2018.

B. C. Ramisetty, What is the link between stringent response, endoribonuclease encoding type II toxin-antitoxin systems and persistence?, Front. Microbiol, vol.7, p.1882, 2016.

L. Sojka, Rapid changes in gene expression: DNA determinants of promoter regulation by the concentration of the transcription initiating NTP in Bacillus subtilis, Nucleic Acids Res, vol.39, pp.4598-4611, 2011.

V. Hauryliuk, Recent functional insights into the role of (p)ppGpp in bacterial physiology, Nat. Rev. Microbiol, vol.13, pp.298-309, 2015.

T. Geiger, Two small (p)ppGpp synthases in Staphylococcus aureus mediate tolerance against cell envelope stress conditions, J. Bacteriol, vol.196, pp.894-902, 2014.

T. Geiger, Role of the (p)ppGpp synthase RSH, a RelA/SpoT homolog, in stringent response and virulence of Staphylococcus aureus, Infect. Immun, vol.78, pp.1873-1883, 2010.

S. Reiss, Global analysis of the Staphylococcus aureus response to mupirocin, Antimicrob. Agents Chemother, vol.56, pp.787-804, 2012.

G. Das and U. Varshney, Peptidyl-tRNA hydrolase and its critical role in protein biosynthesis, Microbiology, vol.152, pp.2191-2195, 2006.

B. P. Conlon, Persister formation in Staphylococcus aureus is associated with ATP depletion, Nat. Microbiol, vol.1, p.16051, 2016.

S. E. Rowe, Reactive oxygen species induce antibiotic tolerance during systemic Staphylococcus aureus infection, Nat. Microbiol, vol.5, pp.282-290, 2020.

Y. Wang, Inactivation of TCA cycle enhances Staphylococcus aureus persister cell formation in stationary phase, Sci. Rep, vol.8, p.10849, 2018.

J. L. Radzikowski, Bacterial persistence is an active sigmaS stress response to metabolic flux limitation, Mol. Syst. Biol, vol.12, p.882, 2016.

M. F. Traxler, D. E. Chang, T. Conway, and . Guanosine, 5?-bispyrophosphate coordinates global gene expression during glucose-lactose diauxie in Escherichia coli, Proc. Natl Acad. Sci. USA, vol.103, pp.2374-2379, 2006.

J. M. Voyich, Insights into mechanisms used by Staphylococcus aureus to avoid destruction by human neutrophils, J. Immunol, vol.175, pp.3907-3919, 2005.

A. M. Palazzolo-ballance, Neutrophil microbicides induce a pathogen survival response in community-associated methicillin-resistant Staphylococcus aureus, J. Immunol, vol.180, pp.500-509, 2008.

C. R. Halsey, Amino acid catabolism in Staphylococcus aureus and the function of carbon catabolite repression, vol.8, pp.1434-1450, 2017.

D. Nguyen, Active starvation responses mediate antibiotic tolerance in biofilms and nutrient-limited bacteria, Science, vol.334, pp.982-986, 2011.
URL : https://hal.archives-ouvertes.fr/pasteur-00722468

V. Dengler, Induction kinetics of the Staphylococcus aureus cell wall stress stimulon in response to different cell wall active antibiotics, BMC Microbiol, vol.11, p.16, 2011.

T. Dorr, K. Lewis, and M. Vulic, SOS response induces persistence to fluoroquinolones in Escherichia coli, PLoS Genet, vol.5, p.1000760, 2009.

C. Miller, SOS response induction by beta-lactams and bacterial defense against antibiotic lethality, Science, vol.305, pp.1629-1631, 2004.

R. T. Cirz, Complete and SOS-mediated response of Staphylococcus aureus to the antibiotic ciprofloxacin, J. Bacteriol, vol.189, pp.531-539, 2007.

V. K. Singh, An insight into the significance of the DnaK heat shock system in Staphylococcus aureus, Int J. Med Microbiol, vol.302, pp.242-252, 2012.

V. K. Singh, Role for dnaK locus in tolerance of multiple stresses in Staphylococcus aureus, Microbiology, vol.153, pp.3162-3173, 2007.

K. Cardoso, DnaK and GroEL are induced in response to antibiotic and heat shock in Acinetobacter baumannii, J. Med. Microbiol, vol.59, pp.1061-1068, 2010.

K. Kannan, The general mode of translation inhibition by macrolide antibiotics, Proc. Natl Acad. Sci. USA, vol.111, pp.15958-15963, 2014.

T. Tenson, M. Lovmar, and M. Ehrenberg, The mechanism of action of macrolides, lincosamides and streptogramin B reveals the nascent peptide exit path in the ribosome, J. Mol. Biol, vol.330, pp.1005-1014, 2003.

M. A. Kohanski, D. J. Dwyer, and J. J. Collins, How antibiotics kill bacteria: from targets to networks, Nat. Rev. Microbiol, vol.8, pp.423-435, 2010.

B. D. Davis, Mechanism of bactericidal action of aminoglycosides, Microbiol. Rev, vol.51, pp.341-350, 1987.

R. G. Sobral, Extensive and genome-wide changes in the transcription profile of Staphylococcus aureus induced by modulating the transcription of the cell wall synthesis gene murF, J. Bacteriol, vol.189, pp.2376-2391, 2007.

K. L. Anderson, Characterization of the Staphylococcus aureus heat shock, cold shock, stringent, and SOS responses and their effects on log-phase mRNA turnover, J. Bacteriol, vol.188, pp.6739-6756, 2006.

X. Wang and X. Zhao, Contribution of oxidative damage to antimicrobial lethality, Antimicrob. Agents Chemother, vol.53, pp.1395-1402, 2009.

M. A. Orman and M. P. Brynildsen, Dormancy is not necessary or sufficient for bacterial persistence, Antimicrob. Agents Chemother, vol.57, pp.3230-3239, 2013.

E. Maisonneuve and K. Gerdes, Molecular mechanisms underlying bacterial persisters, Cell, vol.157, pp.539-548, 2014.

N. R. Cohen, M. A. Lobritz, and J. J. Collins, Microbial persistence and the road to drug resistance, Cell Host Microbe, vol.13, pp.632-642, 2013.

L. R. Mesak, V. Miao, and J. Davies, Effects of subinhibitory concentrations of antibiotics on SOS and DNA repair gene expression in Staphylococcus aureus, Antimicrob. Agents Chemother, vol.52, pp.3394-3397, 2008.

A. Fagerlund, P. E. Granum, and L. S. Havarstein, Staphylococcus aureus competence genes: mapping of the SigH, ComK1 and ComK2 regulons by transcriptome sequencing, Mol. Microbiol, vol.94, pp.557-579, 2014.

M. J. Horsburgh, sigmaB modulates virulence determinant expression and stress resistance: characterization of a functional rsbU strain derived from Staphylococcus aureus 8325-4, J. Bacteriol, vol.184, pp.5457-5467, 2002.

B. T. Bateman, Evaluation of a tetracycline-inducible promoter in Staphylococcus aureus in vitro and in vivo and its application in demonstrating the role of sigB in microcolony formation, Infect. Immun, vol.69, pp.7851-7857, 2001.

R. Snyderman, Biologic and biochemical activities of continuous macrophage cell lines P388D1 and J774.1, J. Immunol, vol.119, pp.2060-2066, 1977.

K. Menck, Isolation of human monocytes by double gradient centrifugation and their differentiation to macrophages in teflon-coated cell culture bags, J. Vis. Exp, vol.91, 2014.

M. Barcia-macay, Pharmacodynamic evaluation of the intracellular activities of antibiotics against Staphylococcus aureus in a model of THP-1 macrophages, Antimicrob. Agents Chemother, vol.50, pp.841-851, 2006.

S. Trouillet, A novel flow cytometry-based assay for the quantification of Staphylococcus aureus adhesion to and invasion of eukaryotic cells, J. Microbiol. Methods, vol.86, pp.145-149, 2011.

S. Lemaire, Activity of moxifloxacin against intracellular communityacquired methicillin-resistant Staphylococcus aureus: comparison with clindamycin, linezolid and co-trimoxazole and attempt at defining an intracellular susceptibility breakpoint, J. Antimicrob. Chemother, vol.66, pp.596-607, 2011.

C. Seral, F. Van-bambeke, and P. Tulkens, Quantitative analysis of gentamicin, azithromycin, telithromycin, ciprofloxacin, moxifloxacin, and oritavancin (LY333328) activities against intracellular Staphylococcus aureus in mouse J774 macrophages, Antimicrob. Agents Chemother, vol.47, pp.2283-2292, 2003.

T. Cokelaer, D. Desvillechabrol, R. Legendre, and M. Cardon, Sequana': a set of snakemake NGS pipelines, J. Open Source Softw, vol.2, 2017.

M. Martin, Cutadapt removes adapter sequences from high-throughput sequencing reads, EMBnet J, vol.17, pp.10-12, 2011.

B. Langmead, Ultrafast and memory-efficient alignment of short DNA sequences to the human genome, Genome Biol, vol.10, p.25, 2009.

Y. Liao, G. K. Smyth, and W. Shi, featureCounts: an efficient general purpose program for assigning sequence reads to genomic features, Bioinformatics, vol.30, pp.923-930, 2014.

. R-core-team, R: a language and environment for statistical computing. R Foundation for Statistical Computing, 2018.

M. I. Love, W. Huber, and S. Anders, Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2, Genome Biol, vol.15, p.550, 2014.

Y. Benjamini and Y. Hochberg, Controlling the false discovery rate: a practical and powerful approach to multiple testing, J. R. Stat. Soc. Ser. B, vol.57, pp.289-300, 1995.

K. J. Livak and T. D. Schmittgen, Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method, Methods, vol.25, pp.402-408, 2001.

. Kegg-orthology, Staphylococcus aureus subsp. aureus NCTC8325, 2018.

. Kegg-pathway, Staphylococcus aureus subsp. aureus NCTC8325, 2020.

S. Utaida, Genome-wide transcriptional profiling of the response of Staphylococcus aureus to cell-wall-active antibiotics reveals a cell-wall-stress stimulon, Microbiology, vol.149, pp.2719-2732, 2003.

F. V. , is Research Director of the Belgian FNRS-FRS; C

, W. is funded by the Deutsche Forschungsgemeinschaft, issue.SFB156

T. T. , The Transcriptome and Epigenome Platform is a member of the France Génomique consortium