No metrics data to plot.
The attempt to load metrics for this article has failed.
The attempt to plot a graph for these metrics has failed.

Staphylococcal Biofilms

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.
  • Author: Michael Otto1
  • Editors: Vincent A. Fischetti2, Richard P. Novick3, Joseph J. Ferretti4, Daniel A. Portnoy5, Julian I. Rood6
    Affiliations: 1: Pathogen Genetics Section, Laboratory of Bacteriology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; 2: The Rockefeller University, New York, NY; 3: Skirball Institute for Molecular Medicine, NYU Medical Center, New York, NY; 4: Department of Microbiology & Immunology, University of Oklahoma Health Science Center, Oklahoma City, OK; 5: Department of Molecular and Cellular Microbiology, University of California, Berkeley, Berkeley, CA; 6: Australian Bacterial Pathogen Program, Department of Microbiology, Monash University, Melbourne, Australia
  • Source: microbiolspec August 2018 vol. 6 no. 4 doi:10.1128/microbiolspec.GPP3-0023-2018
  • Received 15 February 2018 Accepted 10 April 2018 Published 16 August 2018
  • Michael Otto, [email protected]
image of Staphylococcal Biofilms
    Preview this microbiology spectrum article:
    Zoom in

    Staphylococcal Biofilms, Page 1 of 2

    | /docserver/preview/fulltext/microbiolspec/6/4/GPP3-0023-2018-1.gif /docserver/preview/fulltext/microbiolspec/6/4/GPP3-0023-2018-2.gif
  • Abstract:

    Staphylococci, with the leading species and , are the most frequent causes of infections on indwelling medical devices. The biofilm phenotype that those bacteria adopt during device-associated infection facilitates increased resistance to antibiotics and host immune defenses. This review presents and discusses the molecular mechanisms contributing to staphylococcal biofilm development and their in-vivo importance. Furthermore, it summarizes current strategies for the development of therapeutics against staphylococcal biofilm-associated infection.

  • Citation: Otto M. 2018. Staphylococcal Biofilms. Microbiol Spectrum 6(4):GPP3-0023-2018. doi:10.1128/microbiolspec.GPP3-0023-2018.


1. Costerton JW, Lewandowski Z, Caldwell DE, Korber DR, Lappin-Scott HM. 1995. Microbial biofilms. Annu Rev Microbiol 49:711–745 http://dx.doi.org/10.1146/annurev.mi.49.100195.003431. [PubMed]
2. Costerton JW, Stewart PS, Greenberg EP. 1999. Bacterial biofilms: a common cause of persistent infections. Science 284:1318–1322 http://dx.doi.org/10.1126/science.284.5418.1318. [PubMed]
3. Raad I. 1998. Intravascular-catheter-related infections. Lancet 351:893–898 http://dx.doi.org/10.1016/S0140-6736(97)10006-X.
4. Rupp ME. 1997. Coagulase-negative staphylococcal infections: an update regarding recognition and management. Curr Clin Top Infect Dis 17:51–87. [PubMed]
5. Dougherty SH. 1988. Pathobiology of infection in prosthetic devices. Rev Infect Dis 10:1102–1117 http://dx.doi.org/10.1093/clinids/10.6.1102. [PubMed]
6. Hoffmann N, Rasmussen TB, Jensen PO, Stub C, Hentzer M, Molin S, Ciofu O, Givskov M, Johansen HK, Høiby N. 2005. Novel mouse model of chronic Pseudomonas aeruginosa lung infection mimicking cystic fibrosis. Infect Immun 73:2504–2514 http://dx.doi.org/10.1128/IAI.73.4.2504-2514.2005. [PubMed]
7. Resch A, Rosenstein R, Nerz C, Götz F. 2005. Differential gene expression profiling of Staphylococcus aureus cultivated under biofilm and planktonic conditions. Appl Environ Microbiol 71:2663–2676 http://dx.doi.org/10.1128/AEM.71.5.2663-2676.2005. [PubMed]
8. Yao Y, Sturdevant DE, Otto M. 2005. Genomewide analysis of gene expression in Staphylococcus epidermidis biofilms: insights into the pathophysiology of S. epidermidis biofilms and the role of phenol-soluble modulins in formation of biofilms. J Infect Dis 191:289–298 http://dx.doi.org/10.1086/426945. [PubMed]
9. Donlan RM. 2001. Biofilms and device-associated infections. Emerg Infect Dis 7:277–281 http://dx.doi.org/10.3201/eid0702.010226. [PubMed]
10. Metcalf DG, Bowler PG. 2013. Biofilm delays wound healing: a review of the evidence. Burns Trauma 1:5–12 http://dx.doi.org/10.4103/2321-3868.113329. [PubMed]
11. Krismer B, Peschel A. 2011. Does Staphylococcus aureus nasal colonization involve biofilm formation? Future Microbiol 6:489–493 http://dx.doi.org/10.2217/fmb.11.37. [PubMed]
12. Gonzalez T, Biagini Myers JM, Herr AB, Khurana Hershey GK. 2017. Staphylococcal biofilms in atopic dermatitis. Curr Allergy Asthma Rep 17:81 http://dx.doi.org/10.1007/s11882-017-0750-x. [PubMed]
13. Otto M. 2014. Physical stress and bacterial colonization. FEMS Microbiol Rev 38:1250–1270 http://dx.doi.org/10.1111/1574-6976.12088. [PubMed]
14. Rupp ME. 2014. Clinical characteristics of infections in humans due to Staphylococcus epidermidis. Methods Mol Biol 1106:1–16 http://dx.doi.org/10.1007/978-1-62703-736-5_1. [PubMed]
15. Delcaru C, Alexandru I, Podgoreanu P, Grosu M, Stavropoulos E, Chifiriuc MC, Lazar V. 2016. Microbial biofilms in urinary tract infections and prostatitis: etiology, pathogenicity, and combating strategies. Pathogens 5:5 http://dx.doi.org/10.3390/pathogens5040065. [PubMed]
16. Otto M. 2009. Staphylococcus epidermidis: the ‘accidental’ pathogen. Nat Rev Microbiol 7:555–567 http://dx.doi.org/10.1038/nrmicro2182. [PubMed]
17. Wertheim HF, Melles DC, Vos MC, van Leeuwen W, van Belkum A, Verbrugh HA, Nouwen JL. 2005. The role of nasal carriage in Staphylococcus aureus infections. Lancet Infect Dis 5:751–762 http://dx.doi.org/10.1016/S1473-3099(05)70295-4.
18. Datta R, Huang SS. 2008. Risk of infection and death due to methicillin-resistant Staphylococcus aureus in long-term carriers. Clin Infect Dis 47:176–181 http://dx.doi.org/10.1086/589241. [PubMed]
19. Murdoch DR, Roberts SA, Fowler VG Jr, Shah MA, Taylor SL, Morris AJ, Corey GR. 2001. Infection of orthopedic prostheses after Staphylococcus aureus bacteremia. Clin Infect Dis 32:647–649 http://dx.doi.org/10.1086/318704. [PubMed]
20. Wisplinghoff H, Bischoff T, Tallent SM, Seifert H, Wenzel RP, Edmond MB. 2004. Nosocomial bloodstream infections in US hospitals: analysis of 24,179 cases from a pro spective nationwide surveillance study. Clin Infect Dis 39:309–317 http://dx.doi.org/10.1086/421946. [PubMed]
21. Hurlow J, Bowler PG. 2009. Clinical experience with wound biofilm and management: a case series. Ostomy Wound Manage 55:38–49. [PubMed]
22. Hansson C, Hoborn J, Möller A, Swanbeck G. 1995. The microbial flora in venous leg ulcers without clinical signs of infection. Repeated culture using a validated standardised microbiological technique. Acta Derm Venereol 75:24–30. [PubMed]
23. Gjødsbøl K, Christensen JJ, Karlsmark T, Jørgensen B, Klein BM, Krogfelt KA. 2006. Multiple bacterial species reside in chronic wounds: a longitudinal study. Int Wound J 3:225–231 http://dx.doi.org/10.1111/j.1742-481X.2006.00159.x. [PubMed]
24. Alves PM, Al-Badi E, Withycombe C, Jones PM, Purdy KJ, Maddocks SE. 2018. Interaction between Staphylococcus aureus and Pseudomonas aeruginosa is beneficial for colonisation and pathogenicity in a mixed biofilm. Pathog Dis 76:http://dx.doi.org/10.1093/femspd/fty003.
25. O’Toole G, Kaplan HB, Kolter R. 2000. Biofilm formation as microbial development. Annu Rev Microbiol 54:49–79 http://dx.doi.org/10.1146/annurev.micro.54.1.49. [PubMed]
26. Heilmann C. 2011. Adhesion mechanisms of staphylococci. Adv Exp Med Biol 715:105–123 http://dx.doi.org/10.1007/978-94-007-0940-9_7. [PubMed]
27. Bose JL, Lehman MK, Fey PD, Bayles KW. 2012. Contribution of the Staphylococcus aureus Atl AM and GL murein hydrolase activities in cell division, autolysis, and biofilm formation. PLoS One 7:e42244 http://dx.doi.org/10.1371/journal.pone.0042244.
28. Heilmann C, Hussain M, Peters G, Götz F. 1997. Evidence for autolysin-mediated primary attachment of Staphylococcus epidermidis to a polystyrene surface. Mol Microbiol 24:1013–1024 http://dx.doi.org/10.1046/j.1365-2958.1997.4101774.x. [PubMed]
29. Gross M, Cramton SE, Götz F, Peschel A. 2001. Key role of teichoic acid net charge in Staphylococcus aureus colonization of artificial surfaces. Infect Immun 69:3423–3426 http://dx.doi.org/10.1128/IAI.69.5.3423-3426.2001. [PubMed]
30. Schlag M, Biswas R, Krismer B, Kohler T, Zoll S, Yu W, Schwarz H, Peschel A, Götz F. 2010. Role of staphylococcal wall teichoic acid in targeting the major autolysin Atl. Mol Microbiol 75:864–873 http://dx.doi.org/10.1111/j.1365-2958.2009.07007.x. [PubMed]
31. Clarke SR, Foster SJ. 2006. Surface adhesins of Staphylococcus aureus. Adv Microb Physiol 51:187–224 http://dx.doi.org/10.1016/S0065-2911(06)51004-5.
32. Mazmanian SK, Liu G, Ton-That H, Schneewind O. 1999. Staphylococcus aureus sortase, an enzyme that anchors surface proteins to the cell wall. Science 285:760–763 http://dx.doi.org/10.1126/science.285.5428.760. [PubMed]
33. Gill SR, Fouts DE, Archer GL, Mongodin EF, Deboy RT, Ravel J, Paulsen IT, Kolonay JF, Brinkac L, Beanan M, Dodson RJ, Daugherty SC, Madupu R, Angiuoli SV, Durkin AS, Haft DH, Vamathevan J, Khouri H, Utterback T, Lee C, Dimitrov G, Jiang L, Qin H, Weidman J, Tran K, Kang K, Hance IR, Nelson KE, Fraser CM. 2005. Insights on evolution of virulence and resistance from the complete genome analysis of an early methicillin-resistant Staphylococcus aureus strain and a biofilm-producing methicillin-resistant Staphylococcus epidermidis strain. J Bacteriol 187:2426–2438 http://dx.doi.org/10.1128/JB.187.7.2426-2438.2005. [PubMed]
34. Chavakis T, Wiechmann K, Preissner KT, Herrmann M. 2005. Staphylococcus aureus interactions with the endothelium: the role of bacterial “secretable expanded repertoire adhesive molecules” (SERAM) in disturbing host defense systems. Thromb Haemost 94:278–285.
35. Christner M, Franke GC, Schommer NN, Wendt U, Wegert K, Pehle P, Kroll G, Schulze C, Buck F, Mack D, Aepfelbacher M, Rohde H. 2010. The giant extracellular matrix-binding protein of Staphylococcus epidermidis mediates biofilm accumulation and attachment to fibronectin. Mol Microbiol 75:187–207 http://dx.doi.org/10.1111/j.1365-2958.2009.06981.x. [PubMed]
36. Clarke SR, Harris LG, Richards RG, Foster SJ. 2002. Analysis of Ebh, a 1.1-megadalton cell wall-associated fibronectin-binding protein of Staphylococcus aureus. Infect Immun 70:6680–6687 http://dx.doi.org/10.1128/IAI.70.12.6680-6687.2002. [PubMed]
37. Mack D, Fischer W, Krokotsch A, Leopold K, Hartmann R, Egge H, Laufs R. 1996. The intercellular adhesin involved in biofilm accumulation of Staphylococcus epidermidis is a linear beta-1,6-linked glucosaminoglycan: purification and structural analysis. J Bacteriol 178:175–183 http://dx.doi.org/10.1128/jb.178.1.175-183.1996. [PubMed]
38. 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 http://dx.doi.org/10.1074/jbc.M411374200.
39. Vergara-Irigaray M, Maira-Litrán T, Merino N, Pier GB, Penadés JR, Lasa I. 2008. Wall teichoic acids are dispensable for anchoring the PNAG exopolysaccharide to the Staphylococcus aureus cell surface. Microbiology 154:865–877 http://dx.doi.org/10.1099/mic.0.2007/013292-0. [PubMed]
40. Heilmann C, Schweitzer O, Gerke C, Vanittanakom N, Mack D, Götz F. 1996. Molecular basis of intercellular adhesion in the biofilm-forming Staphylococcus epidermidis. Mol Microbiol 20:1083–1091 http://dx.doi.org/10.1111/j.1365-2958.1996.tb02548.x. [PubMed]
41. Gerke C, Kraft A, Süssmuth R, Schweitzer O, Götz F. 1998. Characterization of the N-acetylglucosaminyltransferase activity involved in the biosynthesis of the Staphylococcus epidermidis polysaccharide intercellular adhesin. J Biol Chem 273:18586–18593 http://dx.doi.org/10.1074/jbc.273.29.18586. [PubMed]
42. Conlon KM, Humphreys H, O’Gara JP. 2002. icaR encodes a transcriptional repressor involved in environmental regulation of ica operon expression and biofilm formation in Staphylococcus epidermidis. J Bacteriol 184:4400–4408 http://dx.doi.org/10.1128/JB.184.16.4400-4408.2002. [PubMed]
43. Fitzpatrick F, Humphreys H, O’Gara JP. 2005. Evidence for icaADBC-independent biofilm development mechanism in methicillin-resistant Staphylococcus aureus clinical isolates. J Clin Microbiol 43:1973–1976 http://dx.doi.org/10.1128/JCM.43.4.1973-1976.2005. [PubMed]
44. Kogan G, Sadovskaya I, Chaignon P, Chokr A, Jabbouri S. 2006. Biofilms of clinical strains of Staphylococcus that do not contain polysaccharide intercellular adhesin. FEMS Microbiol Lett 255:11–16 http://dx.doi.org/10.1111/j.1574-6968.2005.00043.x. [PubMed]
45. Rohde H, Burandt EC, Siemssen N, Frommelt L, Burdelski C, Wurster S, Scherpe S, Davies AP, Harris LG, Horstkotte MA, Knobloch JK, Ragunath C, Kaplan JB, Mack D. 2007. Polysaccharide intercellular adhesin or protein factors in biofilm accumulation of Staphylococcus epidermidis and Staphylococcus aureus isolated from prosthetic hip and knee joint infections. Biomaterials 28:1711–1720 http://dx.doi.org/10.1016/j.biomaterials.2006.11.046. [PubMed]
46. Schommer NN, Christner M, Hentschke M, Ruckdeschel K, Aepfelbacher M, Rohde H. 2011. Staphylococcus epidermidis uses distinct mechanisms of biofilm formation to interfere with phagocytosis and activation of mouse macrophage-like cells 774A.1. Infect Immun 79:2267–2276 http://dx.doi.org/10.1128/IAI.01142-10. [PubMed]
47. Wang R, Khan BA, Cheung GY, Bach TH, Jameson-Lee M, Kong KF, Queck SY, Otto M. 2011. Staphylococcus epidermidis surfactant peptides promote biofilm maturation and dissemination of biofilm-associated infection in mice. J Clin Invest 121:238–248 http://dx.doi.org/10.1172/JCI42520. [PubMed]
48. Loughran AJ, Atwood DN, Anthony AC, Harik NS, Spencer HJ, Beenken KE, Smeltzer MS. 2014. Impact of individual extracellular proteases on Staphylococcus aureus biofilm formation in diverse clinical isolates and their isogenic sarA mutants. MicrobiologyOpen 3:897–909 http://dx.doi.org/10.1002/mbo3.214. [PubMed]
49. Pozzi C, Waters EM, Rudkin JK, Schaeffer CR, Lohan AJ, Tong P, Loftus BJ, Pier GB, Fey PD, Massey RC, O’Gara JP. 2012. Methicillin resistance alters the biofilm phenotype and attenuates virulence in Staphylococcus aureus device-associated infections. PLoS Pathog 8:e1002626 http://dx.doi.org/10.1371/journal.ppat.1002626. [PubMed]
50. Corrigan RM, Rigby D, Handley P, Foster TJ. 2007. The role of Staphylococcus aureus surface protein SasG in adherence and biofilm formation. Microbiology 153:2435–2446 http://dx.doi.org/10.1099/mic.0.2007/006676-0. [PubMed]
51. Banner MA, Cunniffe JG, Macintosh RL, Foster TJ, Rohde H, Mack D, Hoyes E, Derrick J, Upton M, Handley PS. 2007. Localized tufts of fibrils on Staphylococcus epidermidis NCTC 11047 are comprised of the accumulation-associated protein. J Bacteriol 189:2793–2804 http://dx.doi.org/10.1128/JB.00952-06. [PubMed]
52. Conrady DG, Brescia CC, Horii K, Weiss AA, Hassett DJ, Herr AB. 2008. A zinc-dependent adhesion module is responsible for intercellular adhesion in staphylococcal biofilms. Proc Natl Acad Sci U S A 105:19456–19461 http://dx.doi.org/10.1073/pnas.0807717105. [PubMed]
53. Geoghegan JA, Corrigan RM, Gruszka DT, Speziale P, O’Gara JP, Potts JR, Foster TJ. 2010. Role of surface protein SasG in biofilm formation by Staphylococcus aureus. J Bacteriol 192:5663–5673 http://dx.doi.org/10.1128/JB.00628-10. [PubMed]
54. Hussain M, Herrmann M, von Eiff C, Perdreau-Remington F, Peters G. 1997. A 140-kilodalton extracellular protein is essential for the accumulation of Staphylococcus epidermidis strains on surfaces. Infect Immun 65:519–524. [PubMed]
55. Rohde H, Burdelski C, Bartscht K, Hussain M, Buck F, Horstkotte MA, Knobloch JK, Heilmann C, Herrmann M, Mack D. 2005. Induction of Staphylococcus epidermidis biofilm formation via proteolytic processing of the accumulation-associated protein by staphylococcal and host proteases. Mol Microbiol 55:1883–1895 http://dx.doi.org/10.1111/j.1365-2958.2005.04515.x. [PubMed]
56. Paharik AE, Kotasinska M, Both A, Hoang TN, Büttner H, Roy P, Fey PD, Horswill AR, Rohde H. 2017. The metalloprotease SepA governs processing of accumulation-associated protein and shapes intercellular adhesive surface properties in Staphylococcus epidermidis. Mol Microbiol 103:860–874 http://dx.doi.org/10.1111/mmi.13594. [PubMed]
57. Macintosh RL, Brittan JL, Bhattacharya R, Jenkinson HF, Derrick J, Upton M, Handley PS. 2009. The terminal A domain of the fibrillar accumulation-associated protein (Aap) of Staphylococcus epidermidis mediates adhesion to human corneocytes. J Bacteriol 191:7007–7016 http://dx.doi.org/10.1128/JB.00764-09. [PubMed]
58. Conrady DG, Wilson JJ, Herr AB. 2013. Structural basis for Zn 2+-dependent intercellular adhesion in staphylococcal biofilms. Proc Natl Acad Sci U S A 110:E202–E211 http://dx.doi.org/10.1073/pnas.1208134110. [PubMed]
59. Gruszka DT, Mendonça CA, Paci E, Whelan F, Hawkhead J, Potts JR, Clarke J. 2016. Disorder drives cooperative folding in a multidomain protein. Proc Natl Acad Sci U S A 113:11841–11846 http://dx.doi.org/10.1073/pnas.1608762113. [PubMed]
60. Gruszka DT, Whelan F, Farrance OE, Fung HK, Paci E, Jeffries CM, Svergun DI, Baldock C, Baumann CG, Brockwell DJ, Potts JR, Clarke J. 2015. Cooperative folding of intrinsically disordered domains drives assembly of a strong elongated protein. Nat Commun 6:7271 http://dx.doi.org/10.1038/ncomms8271. [PubMed]
61. Yarawsky AE, English LR, Whitten ST, Herr AB. 2017. The proline/glycine-rich region of the biofilm adhesion protein Aap forms an extended stalk that resists compaction. J Mol Biol 429:261–279 http://dx.doi.org/10.1016/j.jmb.2016.11.017. [PubMed]
62. Formosa-Dague C, Speziale P, Foster TJ, Geoghegan JA, Dufrêne YF. 2016. Zinc-dependent mechanical properties of Staphylococcus aureus biofilm-forming surface protein SasG. Proc Natl Acad Sci U S A 113:410–415 http://dx.doi.org/10.1073/pnas.1519265113. [PubMed]
63. Cucarella C, Solano C, Valle J, Amorena B, Lasa I, Penadés JR. 2001. Bap, a Staphylococcus aureus surface protein involved in biofilm formation. J Bacteriol 183:2888–2896 http://dx.doi.org/10.1128/JB.183.9.2888-2896.2001. [PubMed]
64. Bowden MG, Chen W, Singvall J, Xu Y, Peacock SJ, Valtulina V, Speziale P, Höök M. 2005. Identification and preliminary characterization of cell-wall-anchored proteins of Staphylococcus epidermidis. Microbiology 151:1453–1464 http://dx.doi.org/10.1099/mic.0.27534-0. [PubMed]
65. Taglialegna A, Navarro S, Ventura S, Garnett JA, Matthews S, Penades JR, Lasa I, Valle J. 2016. Staphylococcal Bap proteins build amyloid scaffold biofilm matrices in response to environmental signals. PLoS Pathog 12:e1005711 http://dx.doi.org/10.1371/journal.ppat.1005711. [PubMed]
66. Rajagopal M, Walker S. 2017. Envelope structures of Gram-positive bacteria. Curr Top Microbiol Immunol 404:1–44. [PubMed]
67. Holland LM, Conlon B, O’Gara JP. 2011. Mutation of tagO reveals an essential role for wall teichoic acids in Staphylococcus epidermidis biofilm development. Microbiology 157:408–418 http://dx.doi.org/10.1099/mic.0.042234-0. [PubMed]
68. Weidenmaier C, Kokai-Kun JF, Kristian SA, Chanturiya T, Kalbacher H, Gross M, Nicholson G, Neumeister B, Mond JJ, Peschel A. 2004. Role of teichoic acids in Staphylococcus aureus nasal colonization, a major risk factor in nosocomial infections. Nat Med 10:243–245 http://dx.doi.org/10.1038/nm991. [PubMed]
69. Whitchurch CB, Tolker-Nielsen T, Ragas PC, Mattick JS. 2002. Extracellular DNA required for bacterial biofilm formation. Science 295:1487 http://dx.doi.org/10.1126/science.295.5559.1487. [PubMed]
70. Otto M. 2013. Staphylococcal infections: mechanisms of biofilm maturation and detachment as critical determinants of pathogenicity. Annu Rev Med 64:175–188 http://dx.doi.org/10.1146/annurev-med-042711-140023. [PubMed]
71. Boles BR, Horswill AR. 2011. Staphylococcal biofilm disassembly. Trends Microbiol 19:449–455 http://dx.doi.org/10.1016/j.tim.2011.06.004. [PubMed]
72. Cheung GY, Joo HS, Chatterjee SS, Otto M. 2014. Phenol-soluble modulins: critical determinants of staphylococcal virulence. FEMS Microbiol Rev 38:698–719 http://dx.doi.org/10.1111/1574-6976.12057. [PubMed]
73. Rautenberg M, Joo HS, Otto M, Peschel A. 2011. Neutrophil responses to staphylococcal pathogens and commensals via the formyl peptide receptor 2 relates to phenol-soluble modulin release and virulence. FASEB J 25:1254–1263 http://dx.doi.org/10.1096/fj.10-175208. [PubMed]
74. Periasamy S, Joo HS, Duong AC, Bach TH, Tan VY, Chatterjee SS, Cheung GY, Otto M. 2012. How Staphylococcus aureus biofilms develop their characteristic structure. Proc Natl Acad Sci U S A 109:1281–1286 http://dx.doi.org/10.1073/pnas.1115006109. [PubMed]
75. Schwartz K, Syed AK, Stephenson RE, Rickard AH, Boles BR. 2012. Functional amyloids composed of phenol soluble modulins stabilize Staphylococcus aureus biofilms. PLoS Pathog 8:e1002744 http://dx.doi.org/10.1371/journal.ppat.1002744. [PubMed]
76. Zheng Y, Joo HS, Nair V, Le KY, Otto M. 2018. Do amyloid structures formed by Staphylococcus aureus phenol-soluble modulins have a biological function? Int J Med Microbiol, 308:675–682 doi:10.1016/j.ijmm.2017.08.010. [PubMed]
77. Shaw L, Golonka E, Potempa J, Foster SJ. 2004. The role and regulation of the extracellular proteases of Staphylococcus aureus. Microbiology 150:217–228 http://dx.doi.org/10.1099/mic.0.26634-0. [PubMed]
78. Boles BR, Horswill AR. 2008. Agr-mediated dispersal of Staphylococcus aureus biofilms. PLoS Pathog 4:e1000052 http://dx.doi.org/10.1371/journal.ppat.1000052. [PubMed]
79. Abraham NM, Jefferson KK. 2012. Staphylococcus aureus clumping factor B mediates biofilm formation in the absence of calcium. Microbiology 158:1504–1512 http://dx.doi.org/10.1099/mic.0.057018-0. [PubMed]
80. McGavin MJ, Zahradka C, Rice K, Scott JE. 1997. Modification of the Staphylococcus aureus fibronectin binding phenotype by V8 protease. Infect Immun 65:2621–2628. [PubMed]
81. Dubin G. 2002. Extracellular proteases of Staphylococcus spp. Biol Chem 383:1075–1086 http://dx.doi.org/10.1515/BC.2002.116. [PubMed]
82. Iwase T, Uehara Y, Shinji H, Tajima A, Seo H, Takada K, Agata T, Mizunoe Y. 2010. Staphylococcus epidermidis Esp inhibits Staphylococcus aureus biofilm formation and nasal colonization. Nature 465:346–349 http://dx.doi.org/10.1038/nature09074. [PubMed]
83. Tang J, Zhou R, Shi X, Kang M, Wang H, Chen H. 2008. Two thermostable nucleases coexisted in Staphylococcus aureus: evidence from mutagenesis and in vitro expression. FEMS Microbiol Lett 284:176–183 http://dx.doi.org/10.1111/j.1574-6968.2008.01194.x. [PubMed]
84. Kiedrowski MR, Kavanaugh JS, Malone CL, Mootz JM, Voyich JM, Smeltzer MS, Bayles KW, Horswill AR. 2011. Nuclease modulates biofilm formation in community-associated methicillin-resistant Staphylococcus aureus. PLoS One 6:e26714 http://dx.doi.org/10.1371/journal.pone.0026714. [PubMed]
85. Beenken KE, Spencer H, Griffin LM, Smeltzer MS. 2012. Impact of extracellular nuclease production on the biofilm phenotype of Staphylococcus aureus under in vitro and in vivo conditions. Infect Immun 80:1634–1638 http://dx.doi.org/10.1128/IAI.06134-11. [PubMed]
86. Davies DG, Parsek MR, Pearson JP, Iglewski BH, Costerton JW, Greenberg EP. 1998. The involvement of cell-to-cell signals in the development of a bacterial biofilm. Science 280:295–298 http://dx.doi.org/10.1126/science.280.5361.295. [PubMed]
87. Vuong C, Saenz HL, Götz F, Otto M. 2000. Impact of the agr quorum-sensing system on adherence to polystyrene in Staphylococcus aureus. J Infect Dis 182:1688–1693 http://dx.doi.org/10.1086/317606. [PubMed]
88. Dunman PM, Murphy E, Haney S, Palacios D, Tucker-Kellogg G, Wu S, Brown EL, Zagursky RJ, Shlaes D, Projan SJ. 2001. Transcription profiling-based identification of Staphylococcus aureus genes regulated by the agr and/or sarA loci. J Bacteriol 183:7341–7353 http://dx.doi.org/10.1128/JB.183.24.7341-7353.2001. [PubMed]
89. Queck SY, Jameson-Lee M, Villaruz AE, Bach TH, Khan BA, Sturdevant DE, Ricklefs SM, Li M, Otto M. 2008. RNAIII-independent target gene control by the agr quorum-sensing system: insight into the evolution of virulence regulation in Staphylococcus aureus. Mol Cell 32:150–158 http://dx.doi.org/10.1016/j.molcel.2008.08.005. [PubMed]
90. Vuong C, Kocianova S, Yao Y, Carmody AB, Otto M. 2004. Increased colonization of indwelling medical devices by quorum-sensing mutants of Staphylococcus epidermidisin vivo. J Infect Dis 190:1498–1505 http://dx.doi.org/10.1086/424487. [PubMed]
91. Xu L, Li H, Vuong C, Vadyvaloo V, Wang J, Yao Y, Otto M, Gao Q. 2006. Role of the luxS quorum-sensing system in biofilm formation and virulence of Staphylococcus epidermidis. Infect Immun 74:488–496 http://dx.doi.org/10.1128/IAI.74.1.488-496.2006. [PubMed]
92. Yu D, Zhao L, Xue T, Sun B. 2012. Staphylococcus aureus autoinducer-2 quorum sensing decreases biofilm formation in an icaR-dependent manner. BMC Microbiol 12:288 http://dx.doi.org/10.1186/1471-2180-12-288. [PubMed]
93. Beenken KE, Mrak LN, Griffin LM, Zielinska AK, Shaw LN, Rice KC, Horswill AR, Bayles KW, Smeltzer MS. 2010. Epistatic relationships between sarA and agr in Staphylococcus aureus biofilm formation. PLoS One 5:e10790 http://dx.doi.org/10.1371/journal.pone.0010790. [PubMed]
94. Tormo MA, Martí M, Valle J, Manna AC, Cheung AL, Lasa I, Penadés JR. 2005. SarA is an essential positive regulator of Staphylococcus epidermidis biofilm development. J Bacteriol 187:2348–2356 http://dx.doi.org/10.1128/JB.187.7.2348-2356.20057. [PubMed]
95. Beenken KE, Blevins JS, Smeltzer MS. 2003. Mutation of sarA in Staphylococcus aureus limits biofilm formation. Infect Immun 71:4206–4211 http://dx.doi.org/10.1128/IAI.71.7.4206-4211.2003. [PubMed]
96. Valle J, Toledo-Arana A, Berasain C, Ghigo JM, Amorena B, Penadés JR, Lasa I. 2003. SarA and not sigmaB is essential for biofilm development by Staphylococcus aureus. Mol Microbiol 48:1075–1087 http://dx.doi.org/10.1046/j.1365-2958.2003.03493.x. [PubMed]
97. Mrak LN, Zielinska AK, Beenken KE, Mrak IN, Atwood DN, Griffin LM, Lee CY, Smeltzer MS. 2012. saeRS and sarA act synergistically to repress protease production and promote biofilm formation in Staphylococcus aureus. PLoS One 7:e38453 http://dx.doi.org/10.1371/journal.pone.0038453. [PubMed]
98. Tamber S, Cheung AL. 2009. SarZ promotes the expression of virulence factors and represses biofilm formation by modulating SarA and agr in Staphylococcus aureus. Infect Immun 77:419–428 http://dx.doi.org/10.1128/IAI.00859-08. [PubMed]
99. Wang L, Li M, Dong D, Bach TH, Sturdevant DE, Vuong C, Otto M, Gao Q. 2008. SarZ is a key regulator of biofilm formation and virulence in Staphylococcus epidermidis. J Infect Dis 197:1254–1262 http://dx.doi.org/10.1086/586714. [PubMed]
100. Kazmierczak MJ, Wiedmann M, Boor KJ. 2005. Alternative sigma factors and their roles in bacterial virulence. Microbiol Mol Biol Rev 69:527–543 http://dx.doi.org/10.1128/MMBR.69.4.527-543.2005. [PubMed]
101. Handke LD, Slater SR, Conlon KM, O’Donnell ST, Olson ME, Bryant KA, Rupp ME, O’Gara JP, Fey PD. 2007. SigmaB and SarA independently regulate polysaccharide intercellular adhesin production in Staphylococcus epidermidis. Can J Microbiol 53:82–91 http://dx.doi.org/10.1139/w06-108. [PubMed]
102. Rom JS, Atwood DN, Beenken KE, Meeker DG, Loughran AJ, Spencer HJ, Lantz TL, Smeltzer MS. 2017. Impact of Staphylococcus aureus regulatory mutations that modulate biofilm formation in the USA300 strain LAC on virulence in a murine bacteremia model. Virulence 8:1776–1790 http://dx.doi.org/10.1080/21505594.2017.1373926. [PubMed]
103. Atwood DN, Loughran AJ, Courtney AP, Anthony AC, Meeker DG, Spencer HJ, Gupta RK, Lee CY, Beenken KE, Smeltzer MS. 2015. Comparative impact of diverse regulatory loci on Staphylococcus aureus biofilm formation. MicrobiologyOpen 4:436–451 http://dx.doi.org/10.1002/mbo3.250. [PubMed]
104. Kies S, Otto M, Vuong C, Götz F. 2001. Identification of the sigB operon in Staphylococcus epidermidis: construction and characterization of a sigB deletion mutant. Infect Immun 69:7933–7936 http://dx.doi.org/10.1128/IAI.69.12.7933-7936.2001. [PubMed]
105. Rupp ME, Ulphani JS, Fey PD, Bartscht K, Mack D. 1999. Characterization of the importance of polysaccharide intercellular adhesin/hemagglutinin of Staphylococcus epidermidis in the pathogenesis of biomaterial-based infection in a mouse foreign body infection model. Infect Immun 67:2627–2632. [PubMed]
106. Rupp ME, Ulphani JS, Fey PD, Mack D. 1999. Characterization of Staphylococcus epidermidis polysaccharide intercellular adhesin/hemagglutinin in the pathogenesis of intravascular catheter-associated infection in a rat model. Infect Immun 67:2656–2659. [PubMed]
107. Rupp ME, Fey PD, Heilmann C, Götz F. 2001. Characterization of the importance of Staphylococcus epidermidis autolysin and polysaccharide intercellular adhesin in the pathogenesis of intravascular catheter-associated infection in a rat model. J Infect Dis 183:1038–1042 http://dx.doi.org/10.1086/319279. [PubMed]
108. McCarthy H, Waters EM, Bose JL, Foster S, Bayles KW, O’Neill E, Fey PD, O’Gara JP. 2016. The major autolysin is redundant for Staphylococcus aureus USA300 LAC JE2 virulence in a murine device-related infection model. FEMS Microbiol Lett 363:363 http://dx.doi.org/10.1093/femsle/fnw087. [PubMed]
109. Merino N, Toledo-Arana A, Vergara-Irigaray M, Valle J, Solano C, Calvo E, Lopez JA, Foster TJ, Penadés JR, Lasa I. 2009. Protein A-mediated multicellular behavior in Staphylococcus aureus. J Bacteriol 191:832–843 http://dx.doi.org/10.1128/JB.01222-08. [PubMed]
110. Vernachio J, Bayer AS, Le T, Chai YL, Prater B, Schneider A, Ames B, Syribeys P, Robbins J, Patti JM. 2003. Anti-clumping factor A immunoglobulin reduces the duration of methicillin-resistant Staphylococcus aureus bacteremia in an experimental model of infective endocarditis. Antimicrob Agents Chemother 47:3400–3406 http://dx.doi.org/10.1128/AAC.47.11.3400-3406.2003. [PubMed]
111. McCrea KW, Hartford O, Davis S, Eidhin DN, Lina G, Speziale P, Foster TJ, Höök M. 2000. The serine-aspartate repeat (Sdr) protein family in Staphylococcus epidermidis. Microbiology 146:1535–1546 http://dx.doi.org/10.1099/00221287-146-7-1535. [PubMed]
112. Arrecubieta C, Toba FA, von Bayern M, Akashi H, Deng MC, Naka Y, Lowy FD. 2009. SdrF, a Staphylococcus epidermidis surface protein, contributes to the initiation of ventricular assist device driveline-related infections. PLoS Pathog 5:e1000411 http://dx.doi.org/10.1371/journal.ppat.1000411. [PubMed]
113. Dastgheyb SS, Villaruz AE, Le KY, Tan VY, Duong AC, Chatterjee SS, Cheung GY, Joo HS, Hickok NJ, Otto M. 2015. Role of phenol-soluble modulins in formation of Staphylococcus aureus biofilms in synovial fluid. Infect Immun 83:2966–2975 http://dx.doi.org/10.1128/IAI.00394-15. [PubMed]
114. Dastgheyb SS, Hammoud S, Ketonis C, Liu AY, Fitzgerald K, Parvizi J, Purtill J, Ciccotti M, Shapiro IM, Otto M, Hickok NJ. 2015. Staphylococcal persistence due to biofilm formation in synovial fluid containing prophylactic cefazolin. Antimicrob Agents Chemother 59:2122–2128 http://dx.doi.org/10.1128/AAC.04579-14. [PubMed]
115. Dastgheyb S, Parvizi J, Shapiro IM, Hickok NJ, Otto M. 2015. Effect of biofilms on recalcitrance of staphylococcal joint infection to antibiotic treatment. J Infect Dis 211:641–650 http://dx.doi.org/10.1093/infdis/jiu514. [PubMed]
116. Peschel A, Otto M. 2013. Phenol-soluble modulins and staphylococcal infection. Nat Rev Microbiol 11:667–673 http://dx.doi.org/10.1038/nrmicro3110. [PubMed]
117. Zielinska AK, Beenken KE, Mrak LN, Spencer HJ, Post GR, Skinner RA, Tackett AJ, Horswill AR, Smeltzer MS. 2012. sarA-mediated repression of protease production plays a key role in the pathogenesis of Staphylococcus aureus USA300 isolates. Mol Microbiol 86:1183–1196 http://dx.doi.org/10.1111/mmi.12048. [PubMed]
118. Rigby KM, DeLeo FR. 2012. Neutrophils in innate host defense against Staphylococcus aureus infections. Semin Immunopathol 34:237–259 http://dx.doi.org/10.1007/s00281-011-0295-3. [PubMed]
119. Wiesner J, Vilcinskas A. 2010. Antimicrobial peptides: the ancient arm of the human immune system. Virulence 1:440–464 http://dx.doi.org/10.4161/viru.1.5.12983. [PubMed]
120. Heinzelmann M, Herzig DO, Swain B, Mercer-Jones MA, Bergamini TM, Polk HC Jr. 1997. Phagocytosis and oxidative-burst response of planktonic Staphylococcus epidermidis RP62A and its non-slime-producing variant in human neutrophils. Clin Diagn Lab Immunol 4:705–710. [PubMed]
121. Donlan RM, Costerton JW. 2002. Biofilms: survival mechanisms of clinically relevant microorganisms. Clin Microbiol Rev 15:167–193 http://dx.doi.org/10.1128/CMR.15.2.167-193.2002. [PubMed]
122. Singh R, Ray P, Das A, Sharma M. 2010. Penetration of antibiotics through Staphylococcus aureus and Staphylococcus epidermidis biofilms. J Antimicrob Chemother 65:1955–1958 http://dx.doi.org/10.1093/jac/dkq257. [PubMed]
123. Mah TF, O’Toole GA. 2001. Mechanisms of biofilm resistance to antimicrobial agents. Trends Microbiol 9:34–39 http://dx.doi.org/10.1016/S0966-842X(00)01913-2.
124. Trampuz A, Zimmerli W. 2006. Antimicrobial agents in orthopaedic surgery: prophylaxis and treatment. Drugs 66:1089–1105 http://dx.doi.org/10.2165/00003495-200666080-00005. [PubMed]
125. Croes S, Beisser PS, Neef C, Bruggeman CA, Stobberingh EE. 2010. Unpredictable effects of rifampin as an adjunctive agent in elimination of rifampin-susceptible and -resistant Staphylococcus aureus strains grown in biofilms. Antimicrob Agents Chemother 54:3907–3912 http://dx.doi.org/10.1128/AAC.01811-09. [PubMed]
126. Meeker DG, Beenken KE, Mills WB, Loughran AJ, Spencer HJ, Lynn WB, Smeltzer MS. 2016. Evaluation of antibiotics active against methicillin-resistant Staphylococcus aureus based on activity in an established biofilm. Antimicrob Agents Chemother 60:5688–5694 http://dx.doi.org/10.1128/AAC.01251-16. [PubMed]
127. Hogan D, Kolter R. 2002. Why are bacteria refractory to antimicrobials? Curr Opin Microbiol 5:472–477 http://dx.doi.org/10.1016/S1369-5274(02)00357-0.
128. Conlon BP, Rowe SE, Lewis K. 2015. Persister cells in biofilm associated infections. Adv Exp Med Biol 831:1–9 http://dx.doi.org/10.1007/978-3-319-09782-4_1. [PubMed]
129. Traber KE, Lee E, Benson S, Corrigan R, Cantera M, Shopsin B, Novick RP. 2008. agr function in clinical Staphylococcus aureus isolates. Microbiology 154:2265–2274 http://dx.doi.org/10.1099/mic.0.2007/011874-0. [PubMed]
130. Thurlow LR, Hanke ML, Fritz T, Angle A, Aldrich A, Williams SH, Engebretsen IL, Bayles KW, Horswill AR, Kielian T. 2011. Staphylococcus aureus biofilms prevent macrophage phagocytosis and attenuate inflammation in vivo. J Immunol 186:6585–6596 http://dx.doi.org/10.4049/jimmunol.1002794. [PubMed]
131. Heim CE, Vidlak D, Scherr TD, Kozel JA, Holzapfel M, Muirhead DE, Kielian T. 2014. Myeloid-derived suppressor cells contribute to Staphylococcus aureus orthopedic biofilm infection. J Immunol 192:3778–3792 http://dx.doi.org/10.4049/jimmunol.1303408. [PubMed]
132. Heim CE, Vidlak D, Odvody J, Hartman CW, Garvin KL, Kielian T. 2017. Human prosthetic joint infections are associated with myeloid-derived suppressor cells (MDSCs): implications for infection persistence. J Orthop Res http://dx.doi.org/10.1002/jor.23806. [PubMed]
133. Gries CM, Bruger EL, Moormeier DE, Scherr TD, Waters CM, Kielian T. 2016. Cyclic di-AMP released from Staphylococcus aureus biofilm induces a macrophage type I interferon response. Infect Immun 84:3564–3574 http://dx.doi.org/10.1128/IAI.00447-16. [PubMed]
134. Prabhakara R, Harro JM, Leid JG, Harris M, Shirtliff ME. 2011. Murine immune response to a chronic Staphylococcus aureus biofilm infection. Infect Immun 79:1789–1796 http://dx.doi.org/10.1128/IAI.01386-10. [PubMed]
135. Kropec A, Maira-Litran T, Jefferson KK, Grout M, Cramton SE, Götz F, Goldmann DA, Pier GB. 2005. Poly- N-acetylglucosamine production in Staphylococcus aureus is essential for virulence in murine models of systemic infection. Infect Immun 73:6868–6876 http://dx.doi.org/10.1128/IAI.73.10.6868-6876.2005. [PubMed]
136. 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 http://dx.doi.org/10.1371/journal.ppat.1002843. [PubMed]
137. Dziewanowska K, Patti JM, Deobald CF, Bayles KW, Trumble WR, Bohach GA. 1999. Fibronectin binding protein and host cell tyrosine kinase are required for internalization of Staphylococcus aureus by epithelial cells. Infect Immun 67:4673–4678. [PubMed]
138. 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 http://dx.doi.org/10.3389/fcimb.2014.00099. [PubMed]
139. Pletzer D, Coleman SR, Hancock RE. 2016. Anti-biofilm peptides as a new weapon in antimicrobial warfare. Curr Opin Microbiol 33:35–40 http://dx.doi.org/10.1016/j.mib.2016.05.016. [PubMed]
140. Peschel A, Sahl HG. 2006. The co-evolution of host cationic antimicrobial peptides and microbial resistance. Nat Rev Microbiol 4:529–536 http://dx.doi.org/10.1038/nrmicro1441. [PubMed]
141. Joo HS, Otto M. 2015. Mechanisms of resistance to antimicrobial peptides in staphylococci. Biochim Biophys Acta 1848(11 Pt B) :3055–3061 http://dx.doi.org/10.1016/j.bbamem.2015.02.009.
142. Romanò CL, Scarponi S, Gallazzi E, Romanò D, Drago L. 2015. Antibacterial coating of implants in orthopaedics and trauma: a classification proposal in an evolving panorama. J Orthop Surg Res 10:157 http://dx.doi.org/10.1186/s13018-015-0294-5. [PubMed]
143. Schaffer AC, Lee JC. 2009. Staphylococcal vaccines and immunotherapies. Infect Dis Clin North Am 23:153–171 http://dx.doi.org/10.1016/j.idc.2008.10.005. [PubMed]
144. Harro JM, Peters BM, O’May GA, Archer N, Kerns P, Prabhakara R, Shirtliff ME. 2010. Vaccine development in Staphylococcus aureus: taking the biofilm phenotype into consideration. FEMS Immunol Med Microbiol 59:306–323 http://dx.doi.org/10.1111/j.1574-695X.2010.00708.x. [PubMed]
145. Søe NH, Jensen NV, Jensen AL, Koch J, Poulsen SS, Pier GB, Johansen HK. 2017. Active and passive immunization against Staphylococcus aureus periprosthetic osteomyelitis in rats. In Vivo 31:45–50 http://dx.doi.org/10.21873/invivo.11023. [PubMed]
146. Shahrooei M, Hira V, Khodaparast L, Khodaparast L, Stijlemans B, Kucharíková S, Burghout P, Hermans PW, Van Eldere J. 2012. Vaccination with SesC decreases Staphylococcus epidermidis biofilm formation. Infect Immun 80:3660–3668 http://dx.doi.org/10.1128/IAI.00104-12. [PubMed]
147. Wittebole X, De Roock S, Opal SM. 2014. A historical overview of bacteriophage therapy as an alternative to antibiotics for the treatment of bacterial pathogens. Virulence 5:226–235 http://dx.doi.org/10.4161/viru.25991. [PubMed]
148. Gutiérrez D, Vandenheuvel D, Martínez B, Rodríguez A, Lavigne R, García P. 2015. Two phages, phiIPLA-RODI and phiIPLA-C1C, lyse mono- and dual-species staphylococcal biofilms. Appl Environ Microbiol 81:3336–3348 http://dx.doi.org/10.1128/AEM.03560-14. [PubMed]
149. Lungren MP, Christensen D, Kankotia R, Falk I, Paxton BE, Kim CY. 2013. Bacteriophage K for reduction of Staphylococcus aureus biofilm on central venous catheter material. Bacteriophage 3:e26825 http://dx.doi.org/10.4161/bact.26825. [PubMed]
150. Cerca N, Oliveira R, Azeredo J. 2007. Susceptibility of Staphylococcus epidermidis planktonic cells and biofilms to the lytic action of Staphylococcus bacteriophage K. Lett Appl Microbiol 45:313–317 http://dx.doi.org/10.1111/j.1472-765X.2007.02190.x. [PubMed]
151. Fischetti VA. 2017. Lysin therapy for Staphylococcus aureus and other bacterial pathogens. Curr Top Microbiol Immunol 409:529–540 http://dx.doi.org/10.1007/82_2015_5005. [PubMed]
152. Schuch R, Khan BK, Raz A, Rotolo JA, Wittekind M. 2017. Bacteriophage lysin CF-301, a potent antistaphylococcal biofilm agent. Antimicrob Agents Chemother 61:61 http://dx.doi.org/10.1128/AAC.02666-16. [PubMed]
153. Kokai-Kun JF, Chanturiya T, Mond JJ. 2007. Lysostaphin as a treatment for systemic Staphylococcus aureus infection in a mouse model. J Antimicrob Chemother 60:1051–1059 http://dx.doi.org/10.1093/jac/dkm347. [PubMed]
154. Hogan S, Zapotoczna M, Stevens NT, Humphreys H, O’Gara JP, O’Neill E. 2017. Potential use of targeted enzymatic agents in the treatment of Staphylococcus aureus biofilm-related infections. J Hosp Infect 96:177–182 http://dx.doi.org/10.1016/j.jhin.2017.02.008. [PubMed]
155. Aguinaga A, Francés ML, Del Pozo JL, Alonso M, Serrera A, Lasa I, Leiva J. 2011. Lysostaphin and clarithromycin: a promising combination for the eradication of Staphylococcus aureus biofilms. Int J Antimicrob Agents 37:585–587 http://dx.doi.org/10.1016/j.ijantimicag.2011.02.009. [PubMed]
156. Wu JA, Kusuma C, Mond JJ, Kokai-Kun JF. 2003. Lysostaphin disrupts Staphylococcus aureus and Staphylococcus epidermidis biofilms on artificial surfaces. Antimicrob Agents Chemother 47:3407–3414 http://dx.doi.org/10.1128/AAC.47.11.3407-3414.2003. [PubMed]
157. Kokai-Kun JF, Chanturiya T, Mond JJ. 2009. Lysostaphin eradicates established Staphylococcus aureus biofilms in jugular vein catheterized mice. J Antimicrob Chemother 64:94–100 http://dx.doi.org/10.1093/jac/dkp145. [PubMed]
158. Donegan EA, Riggs HG Jr. 1974. In vitro incorporation of serine into the staphylococcal cell wall. Infect Immun 10:264–269. [PubMed]
159. Ramasubbu N, Thomas LM, Ragunath C, Kaplan JB. 2005. Structural analysis of dispersin B, a biofilm-releasing glycoside hydrolase from the periodontopathogen Actinobacillus actinomycetemcomitans. J Mol Biol 349:475–486 http://dx.doi.org/10.1016/j.jmb.2005.03.082. [PubMed]
160. Chaignon P, Sadovskaya I, Ragunah C, Ramasubbu N, Kaplan JB, Jabbouri S. 2007. Susceptibility of staphylococcal biofilms to enzymatic treatments depends on their chemical composition. Appl Microbiol Biotechnol 75:125–132 http://dx.doi.org/10.1007/s00253-006-0790-y. [PubMed]
161. Izano EA, Amarante MA, Kher WB, Kaplan JB. 2008. Differential roles of poly- N-acetylglucosamine surface polysaccharide and extracellular DNA in Staphylococcus aureus and Staphylococcus epidermidis biofilms. Appl Environ Microbiol 74:470–476 http://dx.doi.org/10.1128/AEM.02073-07. [PubMed]
162. Dickey SW, Cheung GYC, Otto M. 2017. Different drugs for bad bugs: antivirulence strategies in the age of antibiotic resistance. Nat Rev Drug Discov 16:457–471 http://dx.doi.org/10.1038/nrd.2017.23. [PubMed]

Article metrics loading...



Staphylococci, with the leading species and , are the most frequent causes of infections on indwelling medical devices. The biofilm phenotype that those bacteria adopt during device-associated infection facilitates increased resistance to antibiotics and host immune defenses. This review presents and discusses the molecular mechanisms contributing to staphylococcal biofilm development and their in-vivo importance. Furthermore, it summarizes current strategies for the development of therapeutics against staphylococcal biofilm-associated infection.

Highlighted Text: Show | Hide
Loading full text...

Full text loading...


Image of FIGURE 1

Staphylococcal biofilm development. Attachment of cells to a surface (in the case of surface-attached biofilms) occurs via hydrophobic interactions to an abiotic surface or via surface proteins that bind in a specific fashion to host matrix proteins covering an indwelling medical device. Growth of the biofilm in the proliferation/maturation stage is accompanied by the production of cell-cell adhesive matrix components (such as PIA, eDNA, and proteins), as well as disruptive factors (such as PSMs and degradative secreted enzymes). Those disruptive factors can also cause detachment, a process of great importance for the initiation of complications of biofilm-associated infection, such as bacteremia.

Source: microbiolspec August 2018 vol. 6 no. 4 doi:10.1128/microbiolspec.GPP3-0023-2018
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 2

Predominant staphylococcal biofilm matrix components. The exopolysaccharide PIA (left), produced by many and isolates, is a β1-6-linked homopolymer of -acetylglucosamine. It is synthesized in the cell by the combined activity of the membrane enzymes IcaA and IcaD and likely exported by IcaC. The extracellular surface-bound enzyme IcaB removes a certain percentage (∼15 to 20%) of -acetyl moieties, which gives the otherwise neutral PIA molecule a positive net charge, anchoring PIA to the negatively charged cell surface. In addition to the biosynthetic genes , the PIA biosynthesis locus also contains a regulatory gene, . Several global regulators impact transcription from the and promoters. The accumulation-associated protein (Aap), which is present in and has a homologue in called SasG, is produced as a 220-kD precursor protein, from which the secreted protease SepA cleaves off the N-terminal A-repeat and lectin domains. It is anchored to the cell wall via sortase-catalyzed covalent linkage to lipid II. Mature Aap forms extended fibrils out of B repeat domains, whose polymerization is dependent on Zn ions. Zn is also required for the interconnection of Aap/SasG proteins from different cells, which can happen in an interspecies manner.

Source: microbiolspec August 2018 vol. 6 no. 4 doi:10.1128/microbiolspec.GPP3-0023-2018
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 3

Staphylococcal biofilm-associated infection on medical devices. Mechanisms underlying staphylococcal device-associated infection are depicted in an exemplary fashion for an intravascular catheter-associated biofilm. Many of those are still hypothetical. Biofilm formation on a catheter may originate from bacteria introduced as a contamination during surgery/catheter insertion; those are believed to initiate biofilms on the catheter outside. Alternatively, biofilms in the lumen of the catheter can originate from bacteremia and other infection sites due to hematogenous seeding from those sites. Compared to planktonic growth, biofilms secrete fewer proinflammatory factors, which normally cause considerable responses by innate host defenses, such as phagocyte influx and AMP production. In addition to eliciting fewer such responses, the biofilm matrix provides a shelter from AMPs and phagocyte intrusion. biofilms also attract myeloid-derived suppressor cells (MDSCs), which add to decreasing inflammatory responses, particularly phagocyte influx. Finally, internalization of bacteria, for example, by epithelial cells, can produce SCVs, which are prone to persist and cause recurrent infections.

Source: microbiolspec August 2018 vol. 6 no. 4 doi:10.1128/microbiolspec.GPP3-0023-2018
Permissions and Reprints Request Permissions
Download as Powerpoint

Supplemental Material

No supplementary material available for this content.

This is a required field
Please enter a valid email address
Please check the format of the address you have entered.
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error