Staphylococcus aureus is a serious threat to public health. S. aureus infection can cause acute or long-term persistent infections that are often resistant to antibiotics and are associated with high morbidity and death. Understanding the defensive systems of S. aureus can help clinicians make the best use of antimicrobial drugs and can also help with antimicrobial stewardship. The mechanisms and clinical implications of S. aureus defense systems, as well as potential response systems, were discussed in this study. Because resistance to all currently available antibiotics is unavoidable, new medicines are always being developed. Alternative techniques, such as anti-virulence and bacteriophage therapies, are being researched and may become major tools in the fight against staphylococcal infections in the future, in addition to the development of new small compounds that affect cell viability.

Department of Epidemiology School of Public Health Zhengzhou University No 100 of Science Avenue Zhengzhou 450001 China

Zobrazit více v PubMed

Allegranzi B, Bagheri Nejad S, Combescure C, Graafmans W, Attar H, Donaldson L, Pittet D (2011) Burden of endemic health-care-associated infection in developing countries: systematic review and meta-analysis. Lancet 377:228–241. https://doi.org/10.1016/s0140-6736(10)61458-4 PubMed DOI

Alnaseri H, Arsic B, Schneider JE, Kaiser JC, Scinocca ZC, Heinrichs DE, McGavin MJ (2015) Inducible expression of a resistance-nodulation-division-type efflux pump in Staphylococcus aureus provides resistance to linoleic and arachidonic acids. J Bacteriol 197:1893–1905. https://doi.org/10.1128/jb.02607-14 PubMed DOI PMC

Balasubramanian D, Harper L, Shopsin B, Torres VJ (2017) Staphylococcus aureus pathogenesis in diverse host environments. Pathog Dis 75.  https://doi.org/10.1093/femspd/ftx005

Bhattacharya M, Wozniak DJ, Stoodley P, Hall-Stoodley L (2015) Prevention and treatment of Staphylococcus aureus biofilms. Expert Rev Anti Infect Ther 13:1499–1516. https://doi.org/10.1586/14787210.2015.1100533 PubMed DOI PMC

Boles BR, Horswill AR (2008) Agr-mediated dispersal of Staphylococcus aureus biofilms. PLoS Pathog 4:e1000052. https://doi.org/10.1371/journal.ppat.1000052 PubMed DOI PMC

Boles BR, Horswill AR (2011) Staphylococcal biofilm disassembly. Trends Microbiol 19:449–455. https://doi.org/10.1016/j.tim.2011.06.004 PubMed DOI PMC

Butler MS, Blaskovich MA, Cooper MA (2013) Antibiotics in the clinical pipeline in 2013. J Antibiot (tokyo) 66:571–591. https://doi.org/10.1038/ja.2013.86 DOI

Carbone A et al (2020) Thiazole analogues of the marine alkaloid nortopsentin as inhibitors of bacterial biofilm formation. Molecules 26.  https://doi.org/10.3390/molecules26010081

Carvalhais V, França A, Cerca F, Vitorino R, Pier GB, Vilanova M, Cerca N (2014) Dormancy within Staphylococcus epidermidis biofilms: a transcriptomic analysis by RNA-seq. Appl Microbiol Biotechnol 98:2585–2596. https://doi.org/10.1007/s00253-014-5548-3 PubMed DOI

Cascioferro S, Carbone D, Parrino B, Pecoraro C, Giovannetti E, Cirrincione G, Diana P (2021) Therapeutic strategies to counteract antibiotic resistance in MRSA biofilm-associated infections. ChemMedChem 16:65–80. https://doi.org/10.1002/cmdc.202000677 PubMed DOI

Cascioferro S et al (2019) 2,6-Disubstituted imidazo[2,1-b][1,3,4]thiadiazole derivatives as potent staphylococcal biofilm inhibitors. Eur J Med Chem 167:200–210. https://doi.org/10.1016/j.ejmech.2019.02.007 PubMed DOI

Clement S et al (2005) Evidence of an intracellular reservoir in the nasal mucosa of patients with recurrent Staphylococcus aureus rhinosinusitis. J Infect Dis 192:1023–1028. https://doi.org/10.1086/432735 PubMed DOI

Conlon BP (2014) 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 36:991–996. https://doi.org/10.1002/bies.201400080 PubMed DOI

Conlon BP et al (2013) Activated ClpP kills persisters and eradicates a chronic biofilm infection. Nature 503:365–370. https://doi.org/10.1038/nature12790 PubMed DOI PMC

Conlon BP et al (2016) Persister formation in Staphylococcus aureus is associated with ATP depletion. Nat Microbiol 1.  https://doi.org/10.1038/nmicrobiol.2016.51

Conlon BP, Rowe SE, Lewis K (2015) Persister cells in biofilm associated infections. Adv Exp Med Biol 831:1–9. https://doi.org/10.1007/978-3-319-09782-4_1 PubMed DOI

Costa SS, Mourato C, Viveiros M, Melo-Cristino J, Amaral L, Couto I (2013) Description of plasmid pSM52, harbouring the gene for the Smr efflux pump, and its involvement in resistance to biocides in a meticillin-resistant Staphylococcus aureus strain. Int J Antimicrob Agents 41:490–492. https://doi.org/10.1016/j.ijantimicag.2013.01.003 PubMed DOI

Costerton JW (1999) Introduction to biofilm. Int J Antimicrob Agents 11:217–221; discussion 237–219. https://doi.org/10.1016/s0924-8579(99)00018-7

Craigen B, Dashiff A, Kadouri DE (2011) The use of commercially available alpha-amylase compounds to inhibit and remove Staphylococcus aureus biofilms. Open Microbiol J 5:21–31. https://doi.org/10.2174/1874285801105010021 PubMed DOI PMC

DeMarco CE, Cushing LA, Frempong-Manso E, Seo SM, Jaravaza TA, Kaatz GW (2007) Efflux-related resistance to norfloxacin, dyes, and biocides in bloodstream isolates of Staphylococcus aureus. Antimicrob Agents Chemother 51:3235–3239. https://doi.org/10.1128/aac.00430-07 PubMed DOI PMC

Donlan RM, Costerton JW (2002) Biofilms: survival mechanisms of clinically relevant microorganisms. Clin Microbiol Rev 15:167–193. https://doi.org/10.1128/cmr.15.2.167-193.2002 PubMed DOI PMC

Edwards AM (2012) Phenotype switching is a natural consequence of Staphylococcus aureus replication. J Bacteriol 194:5404–5412. https://doi.org/10.1128/jb.00948-12 PubMed DOI PMC

Fisher RA, Gollan B, Helaine S (2017) Persistent bacterial infections and persister cells. Nat Rev Microbiol 15:453–464. https://doi.org/10.1038/nrmicro.2017.42 PubMed DOI

Flemming HC, Wingender J (2010) The biofilm matrix. Nat Rev Microbiol 8:623–633. https://doi.org/10.1038/nrmicro2415 DOI

Floyd JL, Smith KP, Kumar SH, Floyd JT, Varela MF (2010) LmrS is a multidrug efflux pump of the major facilitator superfamily from Staphylococcus aureus. Antimicrob Agents Chemother 54:5406–5412. https://doi.org/10.1128/aac.00580-10 PubMed DOI PMC

Foster TJ (2017) Antibiotic resistance in Staphylococcus aureus. Current status and future prospects. FEMS Microbiol Rev 41:430–449. https://doi.org/10.1093/femsre/fux007 PubMed DOI

França A, Carvalhais V, Vilanova M, Pier GB, Cerca N (2016) Characterization of an in vitro fed-batch model to obtain cells released from S. epidermidis biofilms. AMB Express 6:23. https://doi.org/10.1186/s13568-016-0197-9

Frempong-Manso E, Raygada JL, DeMarco CE, Seo SM, Kaatz GW (2009) Inability of a reserpine-based screen to identify strains overexpressing efflux pump genes in clinical isolates of Staphylococcus aureus. Int J Antimicrob Agents 33:360–363. https://doi.org/10.1016/j.ijantimicag.2008.10.016 PubMed DOI

Frieri M, Kumar K, Boutin A (2017) Antibiotic resistance. J Infect. Public Health 10:369–378. https://doi.org/10.1016/j.jiph.2016.08.007 DOI

Garcia LG et al (2013) Antibiotic activity against small-colony variants of Staphylococcus aureus: review of in vitro, animal and clinical data. J Antimicrob Chemother 68:1455–1464. https://doi.org/10.1093/jac/dkt072 PubMed DOI

Garzoni C et al (2007) A global view of Staphylococcus aureus whole genome expression upon internalization in human epithelial cells. BMC Genomics 8:171. https://doi.org/10.1186/1471-2164-8-171 PubMed DOI PMC

Gerlach D et al (2018) Methicillin-resistant Staphylococcus aureus alters cell wall glycosylation to evade immunity. Nature 563:705–709. https://doi.org/10.1038/s41586-018-0730-x PubMed DOI

Ghuysen JM (1994) Molecular structures of penicillin-binding proteins and beta-lactamases. Trends Microbiol 2:372–380. https://doi.org/10.1016/0966-842x(94)90614-9 PubMed DOI

Giesbrecht P, Kersten T, Maidhof H, Wecke J (1998) Staphylococcal cell wall: morphogenesis and fatal variations in the presence of penicillin. Microbiol Mol Biol Rev 62:1371–1414. https://doi.org/10.1128/mmbr.62.4.1371-1414.1998 PubMed DOI PMC

Hall-Stoodley L et al (2012) Towards diagnostic guidelines for biofilm-associated infections. FEMS Immunol Med Microbiol 65:127–145. https://doi.org/10.1111/j.1574-695X.2012.00968.x PubMed DOI

Hartman BJ, Tomasz A (1984) Low-affinity penicillin-binding protein associated with beta-lactam resistance in Staphylococcus aureus. J Bacteriol 158:513–516. https://doi.org/10.1128/jb.158.2.513-516.1984 PubMed DOI PMC

Hogan S, Zapotoczna M, Stevens NT, Humphreys H, O’Gara JP, O’Neill E (2016) In vitro approach for identification of the most effective agents for antimicrobial lock therapy in the treatment of intravascular catheter-related infections caused by Staphylococcus aureus. Antimicrob Agents Chemother 60:2923–2931. https://doi.org/10.1128/aac.02885-15 PubMed DOI PMC

Høiby N et al (2015) ESCMID guideline for the diagnosis and treatment of biofilm infections 2014. Clin Microbiol Infect 21(Suppl 1):S1-25. https://doi.org/10.1016/j.cmi.2014.10.024 PubMed DOI

Howlin RP, Brayford MJ, Webb JS, Cooper JJ, Aiken SS, Stoodley P (2015) Antibiotic-loaded synthetic calcium sulfate beads for prevention of bacterial colonization and biofilm formation in periprosthetic infections. Antimicrob Agents Chemother 59:111–120. https://doi.org/10.1128/aac.03676-14 PubMed DOI

Hu H, Ramezanpour M, Hayes AJ, Liu S, Psaltis AJ, Wormald PJ, Vreugde S (2019) Sub-Inhibitory clindamycin and azithromycin reduce S. aureus exoprotein induced toxicity, inflammation, barrier disruption and invasion. J Clin Med 8.  https://doi.org/10.3390/jcm8101617

Kaplan JB et al (2018) Extracellular polymeric substance (EPS)-degrading enzymes reduce staphylococcal surface attachment and biocide resistance on pig skin in vivo. PLoS ONE 13:e0205526. https://doi.org/10.1371/journal.pone.0205526 PubMed DOI PMC

Kiedrowski MR et al (2011) Nuclease modulates biofilm formation in community-associated methicillin-resistant Staphylococcus aureus. PLoS ONE 6:e26714. https://doi.org/10.1371/journal.pone.0026714 PubMed DOI PMC

Kirker KR, Fisher ST, James GA (2015) Potency and penetration of telavancin in staphylococcal biofilms. Int J Antimicrob Agents 46:451–455. https://doi.org/10.1016/j.ijantimicag.2015.05.022 PubMed DOI

Leelaporn A, Firth N, Paulsen IT, Hettiaratchi A, Skurray RA (1995) Multidrug resistance plasmid pSK108 from coagulase-negative staphylococci; relationships to Staphylococcus aureus qacC plasmids. Plasmid 34:62–67. https://doi.org/10.1006/plas.1995.1034 PubMed DOI

Legeay G, Poncin-Epaillard F, Arciola CR (2006) New surfaces with hydrophilic/hydrophobic characteristics in relation to (no)bioadhesion. Int J Artif Organs 29:453–461. https://doi.org/10.1177/039139880602900416 PubMed DOI

Lewis K (2001) Riddle of biofilm resistance. Antimicrob Agents Chemother 45:999–1007. https://doi.org/10.1128/aac.45.4.999-1007.2001 PubMed DOI PMC

Lewis K (2010) Persister cells. Annu Rev Microbiol 64:357–372. https://doi.org/10.1146/annurev.micro.112408.134306 PubMed DOI PMC

Li XZ, Nikaido H (2009) Efflux-mediated drug resistance in bacteria: an update. Drugs 69:1555–1623. https://doi.org/10.2165/11317030-000000000-00000 PubMed DOI PMC

Liu C et al (2011) Clinical practice guidelines by the infectious diseases society of america for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis 52:e18-55. https://doi.org/10.1093/cid/ciq146 PubMed DOI

Liu WT, Chen EZ, Yang L, Peng C, Wang Q, Xu Z, Chen DQ (2021) Emerging resistance mechanisms for 4 types of common anti-MRSA antibiotics in Staphylococcus aureus: a comprehensive review. Microb Pathog 156:104915. https://doi.org/10.1016/j.micpath.2021.104915 PubMed DOI

Ma D et al (2019) The Toxin-Antitoxin MazEF Drives Staphylococcus aureus Biofilm formation, antibiotic tolerance, and chronic infection. mBio 10. https://doi.org/10.1128/mBio.01658-19

Mah TF, O’Toole GA (2001) Mechanisms of biofilm resistance to antimicrobial agents. Trends Microbiol 9:34–39. https://doi.org/10.1016/s0966-842x(00)01913-2 PubMed DOI

Marquez B (2005) Bacterial efflux systems and efflux pumps inhibitors. Biochimie 87:1137–1147. https://doi.org/10.1016/j.biochi.2005.04.012 PubMed DOI

Mascio CT, Alder JD, Silverman JA (2007) Bactericidal action of daptomycin against stationary-phase and nondividing Staphylococcus aureus cells. Antimicrob Agents Chemother 51:4255–4260. https://doi.org/10.1128/aac.00824-07 PubMed DOI PMC

Melter O, Radojevič B (2010) Small colony variants of Staphylococcus aureus–review. Folia Microbiol (praha) 55:548–558. https://doi.org/10.1007/s12223-010-0089-3 DOI

Mihu MR et al (2017) Sustained nitric oxide-releasing nanoparticles interfere with methicillin-resistant Staphylococcus aureus adhesion and biofilm formation in a rat central venous catheter model. Antimicrob Agents Chemother 61.  https://doi.org/10.1128/aac.02020-16

Mishra R, Panda AK, De Mandal S, Shakeel M, Bisht SS, Khan J (2020) Natural anti-biofilm agents: strategies to control biofilm-forming pathogens. Front Microbiol 11:566325. https://doi.org/10.3389/fmicb.2020.566325 PubMed DOI PMC

Mujwar S, Deshmukh R, Harwansh RK, Gupta JK, Gour A (2019) Drug repurposing approach for developing novel therapy against mupirocin-resistant Staphylococcus aureus. Assay Drug Dev Technol 17:298–309. https://doi.org/10.1089/adt.2019.944 PubMed DOI

Musher DM, Baughn RE, Templeton GB, Minuth JN (1977) Emergence of variant forms of Staphylococcus aureus after exposure to gentamicin and infectivity of the variants in experimental animals. J Infect Dis 136:360–369. https://doi.org/10.1093/infdis/136.3.360 PubMed DOI

Muthukrishnan G, Masters EA, Daiss JL, Schwarz EM (2019) Mechanisms of immune evasion and bone tissue colonization that make Staphylococcus aureus the primary pathogen in osteomyelitis. Curr Osteoporos Rep 17:395–404. https://doi.org/10.1007/s11914-019-00548-4 PubMed DOI PMC

Neut D, van der Mei HC, Bulstra SK, Busscher HJ (2007) The role of small-colony variants in failure to diagnose and treat biofilm infections in orthopedics. Acta Orthop 78:299–308. https://doi.org/10.1080/17453670710013843 PubMed DOI

Otto M (2018)Staphylococcal Biofilms. Microbiol Spectr 6.  https://doi.org/10.1128/microbiolspec.GPP3-0023-2018

Pagels M et al (2010) Redox sensing by a Rex-family repressor is involved in the regulation of anaerobic gene expression in Staphylococcus aureus. Mol Microbiol 76:1142–1161. https://doi.org/10.1111/j.1365-2958.2010.07105.x PubMed DOI PMC

Pantosti A, Sanchini A, Monaco M (2007) Mechanisms of antibiotic resistance in Staphylococcus aureus. Future Microbiol 2:323–334. https://doi.org/10.2217/17460913.2.3.323 PubMed DOI

Parrino B et al (2021) 1,2,4-Oxadiazole topsentin analogs as staphylococcal biofilm inhibitors targeting the bacterial transpeptidase sortase A. Eur J Med Chem 209:112892. https://doi.org/10.1016/j.ejmech.2020.112892 PubMed DOI

Parrino B, Schillaci D, Carnevale I, Giovannetti E, Diana P, Cirrincione G, Cascioferro S (2019) Synthetic small molecules as anti-biofilm agents in the struggle against antibiotic resistance. Eur J Med Chem 161:154–178. https://doi.org/10.1016/j.ejmech.2018.10.036 PubMed DOI

Pascoe B, Dams L, Wilkinson TS, Harris LG, Bodger O, Mack D, Davies AP (2014) Dormant cells of Staphylococcus aureus are resuscitated by spent culture supernatant. PLoS ONE 9:e85998. https://doi.org/10.1371/journal.pone.0085998 PubMed DOI PMC

Patti JM, Allen BL, McGavin MJ, Höök M (1994) MSCRAMM-mediated adherence of microorganisms to host tissues. Annu Rev Microbiol 48:585–617. https://doi.org/10.1146/annurev.mi.48.100194.003101 PubMed DOI

Piddock LJ (2006) Clinically relevant chromosomally encoded multidrug resistance efflux pumps in bacteria. Clin Microbiol Rev 19:382–402. https://doi.org/10.1128/cmr.19.2.382-402.2006 PubMed DOI PMC

Piddock LJ, Garvey MI, Rahman MM, Gibbons S (2010) Natural and synthetic compounds such as trimethoprim behave as inhibitors of efflux in Gram-negative bacteria. J Antimicrob Chemother 65:1215–1223. https://doi.org/10.1093/jac/dkq079 PubMed DOI

Potter AD et al (2020) Host nutrient milieu drives an essential role for aspartate biosynthesis during invasive Staphylococcus aureus infection. Proc Natl Acad Sci U S A 117:12394–12401. https://doi.org/10.1073/pnas.1922211117 PubMed DOI PMC

Proctor R (2019) Respiration and Small Colony Variants of Staphylococcus aureus. Microbiol Spectr 7.  https://doi.org/10.1128/microbiolspec.GPP3-0069-2019

Proctor RA, Kahl B, von Eiff C, Vaudaux PE, Lew DP, Peters G (1998) Staphylococcal small colony variants have novel mechanisms for antibiotic resistance. Clin Infect Dis 27(Suppl 1):S68-74. https://doi.org/10.1086/514906 PubMed DOI

Proctor RA, Kriegeskorte A, Kahl BC, Becker K, Löffler B, Peters G (2014) Staphylococcus aureus Small Colony Variants (SCVs): a road map for the metabolic pathways involved in persistent infections. Front Cell Infect Microbiol 4:99. https://doi.org/10.3389/fcimb.2014.00099 PubMed DOI PMC

Proctor RA, von Eiff C, Kahl BC, Becker K, McNamara P, Herrmann M, Peters G (2006) Small colony variants: a pathogenic form of bacteria that facilitates persistent and recurrent infections. Nat Rev Microbiol 4:295–305. https://doi.org/10.1038/nrmicro1384 PubMed DOI

Rabin N, Zheng Y, Opoku-Temeng C, Du Y, Bonsu E, Sintim HO (2015) Agents that inhibit bacterial biofilm formation. Future Med Chem 7:647–671. https://doi.org/10.4155/fmc.15.7 PubMed DOI

Rasko DA, Sperandio V (2010) Anti-virulence strategies to combat bacteria-mediated disease. Nat Rev Drug Discov 9:117–128. https://doi.org/10.1038/nrd3013 PubMed DOI

Rizzato C, Torres J, Kasamatsu E, Camorlinga-Ponce M, Bravo MM, Canzian F, Kato I (2019) Potential role of biofilm formation in the development of digestive tract cancer with special reference to Helicobacter pylori infection. Front Microbiol 10:846. https://doi.org/10.3389/fmicb.2019.00846 PubMed DOI PMC

Roychoudhury S, Dotzlaf JE, Ghag S, Yeh WK (1994) Purification, properties, and kinetics of enzymatic acylation with beta-lactams of soluble penicillin-binding protein 2a. A major factor in methicillin-resistant Staphylococcus aureus. J Biol Chem 269:12067–12073 DOI

Sabatini S, Gosetto F, Manfroni G, Tabarrini O, Kaatz GW, Patel D, Cecchetti V (2011) Evolution from a natural flavones nucleus to obtain 2-(4-Propoxyphenyl)quinoline derivatives as potent inhibitors of the S. aureus NorA efflux pump. J Med Chem 54:5722–5736. https://doi.org/10.1021/jm200370y PubMed DOI

Salem AH, Elkhatib WF, Noreddin AM (2011) Pharmacodynamic assessment of vancomycin-rifampicin combination against methicillin resistant Staphylococcus aureus biofilm: a parametric response surface analysis. J Pharm Pharmacol 63:73–79. https://doi.org/10.1111/j.2042-7158.2010.01183.x PubMed DOI

Schindler BD, Jacinto P, Kaatz GW (2013) Inhibition of drug efflux pumps in Staphylococcus aureus: current status of potentiating existing antibiotics. Future Microbiol 8:491–507. https://doi.org/10.2217/fmb.13.16 PubMed DOI

Schindler BD, Kaatz GW (2016) Multidrug efflux pumps of Gram-positive bacteria. Drug Resist Updat 27:1–13. https://doi.org/10.1016/j.drup.2016.04.003 PubMed DOI

Sendi P, Proctor RA (2009) Staphylococcus aureus as an intracellular pathogen: the role of small colony variants. Trends Microbiol 17:54–58. https://doi.org/10.1016/j.tim.2008.11.004 PubMed DOI

Sendi P, Rohrbach M, Graber P, Frei R, Ochsner PE, Zimmerli W (2006) Staphylococcus aureus small colony variants in prosthetic joint infection. Clin Infect Dis 43:961–967. https://doi.org/10.1086/507633 PubMed DOI

Shahin IG et al (2020) Evaluation of N-phenyl-2-aminothiazoles for treatment of multi-drug resistant and intracellular Staphylococcus aureus infections. Eur J Med Chem 202:112497. https://doi.org/10.1016/j.ejmech.2020.112497 PubMed DOI

Shan Y, Brown Gandt A, Rowe SE, Deisinger JP, Conlon BP, Lewis K (2017) ATP-dependent persister formation in Escherichia coli. mBio 8.  https://doi.org/10.1128/mBio.02267-16

Sharma D, Misba L, Khan AU (2019) Antibiotics versus biofilm: an emerging battleground in microbial communities. Antimicrob Resist Infect Control 8:76. https://doi.org/10.1186/s13756-019-0533-3 PubMed DOI PMC

Sievert DM et al (2013) Antimicrobial-resistant pathogens associated with healthcare-associated infections: summary of data reported to the National Healthcare Safety Network at the Centers for Disease Control and Prevention, 2009–2010. Infect Control Hosp Epidemiol 34:1–14. https://doi.org/10.1086/668770 PubMed DOI

Song R et al (2020) Naphthoquinone-derivative as a synthetic compound to overcome the antibiotic resistance of methicillin-resistant S. aureus. Commun Biol 3:529.  https://doi.org/10.1038/s42003-020-01261-0

Stapleton PD, Taylor PW (2002) Methicillin resistance in Staphylococcus aureus: mechanisms and modulation. Sci Prog 85:57–72. https://doi.org/10.3184/003685002783238870 PubMed DOI PMC

Stavri M, Piddock LJ, Gibbons S (2007) Bacterial efflux pump inhibitors from natural sources. J Antimicrob Chemother 59:1247–1260. https://doi.org/10.1093/jac/dkl460 PubMed DOI

Stepanović S, Vuković D, Jezek P, Pavlović M, Svabic-Vlahović M (2001) Influence of dynamic conditions on biofilm formation by staphylococci. Eur J Clin Microbiol Infect Dis 20:502–504. https://doi.org/10.1007/s100960100534 PubMed DOI

Stewart PS, Costerton JW (2001) Antibiotic resistance of bacteria in biofilms. Lancet 358:135–138. https://doi.org/10.1016/s0140-6736(01)05321-1 PubMed DOI

Styers D, Sheehan DJ, Hogan P, Sahm DF (2006) Laboratory-based surveillance of current antimicrobial resistance patterns and trends among Staphylococcus aureus: 2005 status in the United States. Ann Clin Microbiol Antimicrob 5:2. https://doi.org/10.1186/1476-0711-5-2 PubMed DOI PMC

Thammavongsa V, Rauch S, Kim HK, Missiakas DM, Schneewind O (2015) Protein A-neutralizing monoclonal antibody protects neonatal mice against Staphylococcus aureus. Vaccine 33:523–526. https://doi.org/10.1016/j.vaccine.2014.11.051 PubMed DOI

Tubby S, Wilson M, Wright JA, Zhang P, Nair SP (2013) Staphylococcus aureus small colony variants are susceptible to light activated antimicrobial agents. BMC Microbiol 13:201. https://doi.org/10.1186/1471-2180-13-201 PubMed DOI PMC

Tuchscherr L et al (2010) Staphylococcus aureus small-colony variants are adapted phenotypes for intracellular persistence. J Infect Dis 202:1031–1040. https://doi.org/10.1086/656047 PubMed DOI

Tuchscherr L et al (2011) Staphylococcus aureus phenotype switching: an effective bacterial strategy to escape host immune response and establish a chronic infection. EMBO Mol Med 3:129–141. https://doi.org/10.1002/emmm.201000115 PubMed DOI PMC

Valle J, Latasa C, Gil C, Toledo-Arana A, Solano C, Penadés JR, Lasa I (2012) Bap, a biofilm matrix protein of Staphylococcus aureus prevents cellular internalization through binding to GP96 host receptor. PLoS Pathog 8:e1002843. https://doi.org/10.1371/journal.ppat.1002843 PubMed DOI PMC

Van Kerckhoven M et al (2016) Characterizing the in vitro biofilm phenotype of Staphylococcus epidermidis isolates from central venous catheters. J Microbiol Methods 127:95–101. https://doi.org/10.1016/j.mimet.2016.05.009 PubMed DOI

Vanhommerig E et al (2014) Comparison of biofilm formation between major clonal lineages of methicillin resistant Staphylococcus aureus. PLoS ONE 9:e104561. https://doi.org/10.1371/journal.pone.0104561 PubMed DOI PMC

Vergidis P et al (2011) Treatment with linezolid or vancomycin in combination with rifampin is effective in an animal model of methicillin-resistant Staphylococcus aureus foreign body osteomyelitis. Antimicrob Agents Chemother 55:1182–1186. https://doi.org/10.1128/aac.00740-10 PubMed DOI

von Eiff C (2008) Staphylococcus aureus small colony variants: a challenge to microbiologists and clinicians. Int J Antimicrob Agents 31:507–510. https://doi.org/10.1016/j.ijantimicag.2007.10.026 DOI

von Eiff C, Becker K, Metze D, Lubritz G, Hockmann J, Schwarz T, Peters G (2001) Intracellular persistence of Staphylococcus aureus small-colony variants within keratinocytes: a cause for antibiotic treatment failure in a patient with darier’s disease. Clin Infect Dis 32:1643–1647. https://doi.org/10.1086/320519 DOI

von Eiff C, Bettin D, Proctor RA, Rolauffs B, Lindner N, Winkelmann W, Peters G (1997) Recovery of small colony variants of Staphylococcus aureus following gentamicin bead placement for osteomyelitis. Clin Infect Dis 25:1250–1251. https://doi.org/10.1086/516962 DOI

Vuong C, Kocianova S, Voyich JM, Yao Y, Fischer ER, DeLeo FR, Otto M (2004) A crucial role for exopolysaccharide modification in bacterial biofilm formation, immune evasion, and virulence. J Biol Chem 279:54881–54886. https://doi.org/10.1074/jbc.M411374200 PubMed DOI

Waters EM, Rowe SE, O’Gara JP, Conlon BP (2016) Convergence of Staphylococcus aureus persister and biofilm research: can biofilms be defined as communities of adherent persister cells? PLoS Pathog 12:e1006012. https://doi.org/10.1371/journal.ppat.1006012 PubMed DOI PMC

Webber MA, Piddock LJ (2003) The importance of efflux pumps in bacterial antibiotic resistance. J Antimicrob Chemother 51:9–11. https://doi.org/10.1093/jac/dkg050 DOI

Wells CM, Beenken KE, Smeltzer MS, Courtney HS, Jennings JA, Haggard WO (2018) Ciprofloxacin and rifampin dual antibiotic-loaded biopolymer chitosan sponge for bacterial inhibition. Mil Med 183:433–444. https://doi.org/10.1093/milmed/usx150 PubMed DOI

Wood TK, Knabel SJ, Kwan BW (2013) Bacterial persister cell formation and dormancy. Appl Environ Microbiol 79:7116–7121. https://doi.org/10.1128/aem.02636-13 PubMed DOI PMC

Zapotoczna M, McCarthy H, Rudkin JK, O’Gara JP, O’Neill E (2015) An essential role for coagulase in Staphylococcus aureus biofilm development reveals new therapeutic possibilities for device-related infections. J Infect Dis 212:1883–1893. https://doi.org/10.1093/infdis/jiv319 PubMed DOI

Zhang HZ, Hackbarth CJ, Chansky KM, Chambers HF (2001) A proteolytic transmembrane signaling pathway and resistance to beta-lactams in staphylococci. Science 291:1962–1965. https://doi.org/10.1126/science.1055144 PubMed DOI

Zheng Z, Stewart PS (2002) Penetration of rifampin through Staphylococcus epidermidis biofilms. Antimicrob Agents Chemother 46:900–903. https://doi.org/10.1128/aac.46.3.900-903.2002 PubMed DOI PMC

Zimmerli W (2014) Clinical presentation and treatment of orthopaedic implant-associated infection. J Intern Med 276:111–119. https://doi.org/10.1111/joim.12233 PubMed DOI