Methicillin resistance and the biofilm phenotype in staphylococcus aureus

Frontiers in Cellular and Infection Microbiology

Volumn 5, Issue , 2015, Pages

  McCarthy, Hannah ^a   Rudkin, Justine K ^a   Black, Nikki S ^a   Gallagher, Laura ^a   O'Neill, Eoghan ^b   O'Gara, James P ^a  

^a NATIONAL UNIVERSITY OF IRELAND   (Ireland)

^b ROYAL COLLEGE OF SURGEONS IN IRELAND   (Ireland)

Author keywords

Atl; Biofilm; C di AMP; LPXTG proteins; MecA; Methicillin resistance; PIA; Staphylococcus aureus

Indexed keywords

AUTOLYSIN; FIBRONECTIN BINDING PROTEIN;

BACTERIAL VIRULENCE; BIOFILM; DOWN REGULATION; ENZYME ACTIVITY; GENE CONTROL; GENE MUTATION; METHICILLIN RESISTANT STAPHYLOCOCCUS AUREUS; METHICILLIN SUSCEPTIBLE STAPHYLOCOCCUS AUREUS; NONHUMAN; NUCLEOTIDE SEQUENCE; PENICILLIN RESISTANCE; PHENOTYPE; PROTEIN EXPRESSION; QUORUM SENSING; REVIEW; SCANNING ELECTRON MICROSCOPY;

EID: 85005773700     PISSN: None     EISSN: 22352988     Source Type: Journal    
DOI: 10.3389/fcimb.2015.00001     Document Type: Review

References (109)

1. Abraham, J., Mansour, C., Veledar, E., Khan, B., and Lerakis, S. (2004). Staphylococcus aureus bacteremia and endocarditis: the Grady Memorial Hospital experience with methicillin-sensitive S aureus and methicillin-resistant S aureus bacteremia. Am. Heart J. 147, 536-539. doi: 10.1016/j.ahj.2003.09.018.
2. Beenken, K. E., Blevins, J. S., and Smeltzer, M. S. (2003). Mutation of sarA in Staphylococcus aureus limits biofilm formation. Infect. Immun. 71, 4206-4211. doi: 10.1128/IAI.71.7.4206-4211.2003
3. Beenken, K. E., Dunman, P. M., McAleese, F., Macapagal, D., Murphy, E., Projan, S. J., et al. (2004). Global gene expression in Staphylococcus aureus biofilms. J. Bacteriol. 186, 4665-4684. doi: 10.1128/JB.186.14.4665-4684.2004
4. Beenken, K. E., Spencer, H., Griffin, L. M., and Smeltzer, M. S. (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. doi: 10.1128/IAI.06134-11
5. Biswas, R., Voggu, L., Simon, U. K., Hentschel, P., Thumm, G., and Gotz, F. (2006). Activity of the major staphylococcal autolysin Atl. FEMS Microbiol. Lett. 259, 260-268. doi: 10.1111/j.1574-6968.2006.00281.x
6. Boles, B. R., and Horswill, A. R. (2008). Agr-mediated dispersal of Staphylococcus aureus biofilms. PLoS Pathog. 4:e1000052. doi: 10.1371/journal.ppat. 1000052
7. Boles, B. R., Thoendel, M., Roth, A. J., and Horswill, A. R. (2010). Identification of genes involved in polysaccharide-independent Staphylococcus aureus biofilm formation. PLoS ONE 5:e10146. doi: 10.1371/journal.pone.0010146
8. Bose, J. L., Lehman, M. K., Fey, P. D., and Bayles, K. W. (2012). Contribution of the Staphylococcus aureus Atl AM and GL murein hydrolase activities in cell division, autolysis, and biofilm formation. PLoS ONE 7:e42244. doi: 10.1371/journal.pone.0042244
9. Christner, M., Heinze, C., Busch, M., Franke, G., Hentschke, M., Bayard duhring, S., et al. (2012). sarA negatively regulates Staphylococcus epidermidis biofilm formation by modulating expression of 1 MDa extracellular matrix binding protein and autolysis-dependent release of eDNA. Mol. Microbiol. 86, 394-410. doi: 10.1111/j.1365-2958.2012.08203.x
10. Claret, L., Miquel, S., Vieille, N., Ryjenkov, D. A., Gomelsky, M., and Darfeuille-Michaud, A. (2007). The flagellar sigma factor FliA regulates adhesion and invasion of Crohn disease-associated Escherichia coli via a cyclic dimeric GMP-dependent pathway. J. Biol. Chem. 282, 33275-33283. doi: 10.1074/jbc.M702800200
11. Collins, J., Rudkin, J., Recker, M., Pozzi, C., O'Gara, J. P., and Massey, R. C. (2010). Offsetting virulence and antibiotic resistance costs by MRSA. ISME J. 4, 577-584. doi: 10.1038/ismej.2009.151
12. Conlon, B. P., Geoghegan, J. A., Waters, E. M., McCarthy, H., Rowe, S. E., Davies, J. R., et al. (2014). Role for the a domain of unprocessed Accumulation-Associated Protein (Aap) in the attachment phase of the Staphylococcus epidermidis biofilm phenotype. J. Bacteriol. 196, 4268-4275. doi: 10.1128/JB.01946-14
13. Conlon, K. M., Humphreys, H., and O'Gara, J. P. (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. doi: 10.1128/JB.184.16.4400-4408.2002
14. Conrady, D. G., Brescia, C. C., Horii, K., Weiss, A. A., Hassett, D. J., and Herr, A. B. (2008). A zinc-dependent adhesion module is responsible for intercellular adhesion in staphylococcal biofilms. Proc. Natl. Acad. Sci. U.S.A. 105, 19456-19461. doi: 10.1073/pnas.0807717105
15. Conrady, D. G., Wilson, J. J., and Herr, A. B. (2013). Structural basis for Zn2+- dependent intercellular adhesion in staphylococcal biofilms. Proc. Natl. Acad. Sci. U.S.A. 110, E202-E211. doi: 10.1073/pnas.1208134110
16. Corrigan, R. M., Abbott, J. C., Burhenne, H., Kaever, V., and Grundling, A. (2011). c-di-AMP is a new second messenger in Staphylococcus aureus with a role in controlling cell size and envelope stress. PLoS Pathog. 7:e1002217. doi: 10.1371/journal.ppat.1002217
17. Corrigan, R. M., Campeotto, I., Jeganathan, T., Roelofs, K. G., Lee, V. T., and Gründling, A. (2013). Systematic identification of conserved bacterial c-di- AMP receptor proteins. Proc. Natl. Acad. Sci. U.S.A. 110, 9084-9089. doi: 10.1073/pnas.1300595110
18. Corrigan, R. M., Rigby, D., Handley, P., and Foster, T. J. (2007). The role of Staphylococcus aureus surface protein SasG in adherence and biofilm formation. Microbiology 153, 2435-2446. doi: 10.1099/mic.0.2007/006676-0
19. Cramton, S. E., Gerke, C., Schnell, N. F., Nichols, W. W., and Götz, F. (1999). The intercellular adhesion (ica) locus is present in Staphylococcus aureus and is required for biofilm formation. Infect. Immun. 67, 5427-5433.
20. Cramton, S. E., Ulrich, M., Gotz, F., and Doring, G. (2001). Anaerobic conditions induce expression of polysaccharide intercellular adhesin in Staphylococcus aureus and Staphylococcus epidermidis. Infect. Immun. 69, 4079-4085. doi: 10.1128/IAI.69.6.4079-4085.2001
21. Cucarella, C., Solano, C., Valle, J., Amorena, B., Lasa, I., and Penades, J. R. (2001). Bap, a Staphylococcus aureus surface protein involved in biofilm formation. J. Bacteriol. 183, 2888-2896. doi: 10.1128/JB.183.9.2888-2896.2001
22. Cucarella, C., Tormo, M. A., Ubeda, C., Trotonda, M. P., Monzón, M., Peris, C., et al. (2004). Role of biofilm-associated protein bap in the pathogenesis of bovine Staphylococcus aureus. Infect. Immun. 72, 2177-2185. doi: 10.1128/IAI.72.4.2177-2185.2004
23. Dastgheyb, S., Parvizi, J., Shapiro, I. M., Hickok, N. J., and Otto, M. (2014). Effect of biofilms on recalcitrance of staphylococcal joint infection to antibiotic treatment. J. Infect. Dis. doi: 10.1093/infdis/jiu514. [Epub ahead of print].
24. Davies, D. (2003). Understanding biofilm resistance to antibacterial agents. Nat. Rev. Drug Discov. 2, 114-122. doi: 10.1038/nrd1008
25. Dengler, V., McCallum, N., Kiefer, P., Christen, P., Patrignani, A., Vorholt, J. A., et al. (2013). Mutation in the C-Di-AMP Cyclase dacA affects fitness and resistance of methicillin resistant Staphylococcus aureus. PLoS ONE 8:e73512. doi: 10.1371/journal.pone.0073512
26. Donlan, R. M., and Costerton, J. W. (2002). Biofilms: survival mechanisms of clinically relevant microorganisms. Clin. Microbiol. Rev. 15, 167-193. doi: 10.1128/CMR.15.2.167-193.2002
27. Dordel, J., Kim, C., Chung, M., Pardos de la Gandara, M., Holden, M. T., Parkhill, J., et al. (2014). Novel determinants of antibiotic resistance: identification of mutated loci in highly methicillin-resistant subpopulations of methicillinresistant Staphylococcus aureus. MBio 5:e01000. doi: 10.1128/mBio.01000-13
28. Fitzpatrick, F., Humphreys, H., and O'Gara, J. P. (2006). Environmental regulation of biofilm development in methicillin-resistant and methicillin-susceptible Staphylococcus aureus clinical isolates. J. Hosp. Infect. 62, 120-122. doi: 10.1016/j.jhin.2005.06.004
29. Fitzpatrick, F., Humphreys, H., and O'Gara, J. P. (2005). Evidence for icaADBC-independent biofilm development mechanism in methicillinresistant Staphylococcus aureus clinical isolates. J. Clin. Microbiol. 43, 1973-1976. doi: 10.1128/JCM.43.4.1973-1976.2005
30. Foulston, L., Elsholz, A. K., Defrancesco, A. S., and Losick, R. (2014). The extracellular matrix of Staphylococcus aureus biofilms comprises cytoplasmic proteins that associate with the cell surface in response to decreasing pH. MBio 5:e01667-14. doi: 10.1128/mBio.01667-14
31. Fournier, B., and Hooper, D. C. (2000). A new two-component regulatory system involved in adhesion, autolysis, and extracellular proteolytic activity of Staphylococcus aureus. J. Bacteriol. 182, 3955-3964. doi: 10.1128/JB.182.14.3955-3964.2000
32. Fowler, V. G. J., Fey, P. D., Reller, L. B., Chamis, A. L., Corey, G. R., and Rupp, M. E. (2001). The intercellular adhesin locus ica is present in clinical isolates of Staphylococcus aureus from bacteremic patients with infected and uninfected prosthetic joints. Med. Microbiol. Immunol. 189, 127-131. doi: 10.1007/s430- 001-8018-5
33. Geoghegan, J. A., Corrigan, R. M., Gruszka, D. T., Speziale, P., O'Gara, J. P., Potts, J. R., et al. (2010). Role of surface protein SasG in biofilm formation by Staphylococcus aureus. J. Bacteriol. 192, 5663-5673. doi: 10.1128/JB.00628-10
34. Geoghegan, J. A., Monk, I. R., O'Gara, J. P., and Foster, T. J. (2013). Subdomains N2N3 of fibronectin binding protein a mediate Staphylococcus aureus biofilm formation and adherence to fibrinogen using distinct mechanisms. J. Bacteriol. 195, 2675-2683. doi: 10.1128/JB.02128-12
35. Götz, F. (2002). Staphylococcus and biofilms. Mol. Microbiol. 43, 1367-1378. doi: 10.1046/j.1365-2958.2002.02827.x
36. Griffiths, J. M., and O'Neill, A. J. (2012). Loss of function of the gdpP protein leads to joint beta-lactam/glycopeptide tolerance in Staphylococcus aureus. Antimicrob. Agents Chemother. 56, 579-581. doi: 10.1128/AAC.05148-11
37. Gruszka, D. T., Wojdyla, J. A., Bingham, R. J., Turkenburg, J. P., Manfield, I. W., Steward, A., et al. (2012). Staphylococcal biofilm-forming protein has a contiguous rod-like structure. Proc. Natl. Acad. Sci. U.S.A. 109, E1011-E1018. doi: 10.1073/pnas.1119456109
38. Hall-Stoodley, L., Costerton, J. W., and Stoodley, P. (2004). Bacterial biofilms: from the natural environment to infectious diseases. Nat. Rev. Microbiol. 2, 95-108. doi: 10.1038/nrmicro821
39. Hammond, A. A., Miller, K. G., Kruczek, C. J., Dertien, J., Colmer-Hamood, J. A., Griswold, J. A., et al. (2011). An in vitro biofilm model to examine the effect of antibiotic ointments on biofilms produced by burn wound bacterial isolates. Burns 37, 312-321. doi: 10.1016/j.burns.2010.09.017
40. Heilmann, C., Gerke, C., Perdreau-Remington, F., and Götz, F. (1996a). Characterization of Tn917 insertion mutants of Staphylococcus epidermidis affected in biofilm formation. Infect. Immun. 64, 277-282.
41. Heilmann, C., and Götz, F. (1998). Further characterization of Staphylococcus epidermidis transposon mutants deficient in primary attachment or intercellular adhesion. Zentralbl. Bakteriol. 287, 69-83. doi: 10.1016/S0934-8840(98)80149-7
42. Heilmann, C., Hussain, M., Peters, G., and Götz, F. (1997). Evidence for autolysin-mediated primary attachment of Staphylococcus epidermidis to a polystyrene surface. Mol. Microbiol. 24, 1013-1024. doi: 10.1046/j.1365- 2958.1997.4101774.x
43. Heilmann, C., Schweitzer, O., Gerke, C., Vanittanakom, N., Mack, D., and Götz, F. (1996b). Molecular basis of intercellular adhesion in the biofilm-forming Staphylococcus epidermidis. Mol. Microbiol. 20, 1083-1091. doi: 10.1111/j.1365- 2958.1996.tb02548.x
44. Høiby, N., Bjarnsholt, T., Givskov, M., Molin, S., and Ciofu, O. (2010). Antibiotic resistance of bacterial biofilms. Int. J. Antimicrob. Agents 35, 322-332. doi: 10.1016/j.ijantimicag.2009.12.011
45. Houston, P., Rowe, S. E., Pozzi, C., Waters, E. M., and O'Gara, J. P. (2011). Essential role for the major autolysin in the fibronectin-binding protein-mediated Staphylococcus aureus biofilm phenotype. Infect. Immun. 79, 1153-1165. doi: 10.1128/IAI.00364-10
46. Hussain, M., Herrmann, M., Von eiff, C., Perdreau-Remington, F., and Peters, G. (1997). A 140-kilodalton extracellular protein is essential for the accumulation of Staphylococcus epidermidis strains on surfaces. Infect. Immun. 65, 519-524.
47. Izano, E. A., Amarante, M. A., Kher, W. B., and Kaplan, J. B. (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. doi: 10.1128/AEM.02073-07
48. Joo, H. S., and Otto, M. (2012). Molecular basis of in vivo biofilm formation by bacterial pathogens. Chem. Biol. 19, 1503-1513. doi: 10.1016/j.chembiol.2012.10.022
49. Kaito, C., Omae, Y., Matsumoto, Y., Nagata, M., Yamaguchi, H., Aoto, T., et al. (2008). A novel gene, fudoh, in the SCCmec region suppresses the colony spreading ability and virulence of Staphylococcus aureus. PLoS ONE 3:e3921. doi: 10.1371/journal.pone.0003921
50. Kaito, C., Saito, Y., Ikuo, M., Omae, Y., Mao, H., Nagano, G., et al. (2013). Mobile genetic element SCCmec-encoded psm-mec RNA suppresses translation of agrA and attenuates MRSA virulence. PLoS Pathog. 9:e1003269. doi: 10.1371/journal.ppat.1003269
51. Kaito, C., Saito, Y., Nagano, G., Ikuo, M., Omae, Y., Hanada, Y., et al. (2011). Transcription and translation products of the cytolysin gene psm-mec on the mobile genetic element SCCmec regulate Staphylococcus aureus virulence. PLoS Pathog. 7:e1001267. doi: 10.1371/journal.ppat.1001267
52. Karlsson, A., Saravia-Otten, P., Tegmark, K., Morfeldt, E., and Arvidson, S. (2001). Decreased amounts of cell wall-associated protein A and fibronectin-binding proteins in Staphylococcus aureus sarA mutants due to up-regulation of extracellular proteases. Infect. Immun. 69, 4742-4748. doi: 10.1128/IAI.69.8.4742- 4748.2001
53. Keaton, M. A., Rosato, R. R., Plata, K. B., Singh, C. R., and Rosato, A. E. (2013). Exposure of clinical MRSA heterogeneous strains to beta-lactams redirects metabolism to optimize energy production through the TCA cycle. PLoS ONE 8:e71025. doi: 10.1371/journal.pone.0071025
54. Kiedrowski, M. R., Kavanaugh, J. S., Malone, C. L., Mootz, J. M., Voyich, J. M., Smeltzer, M. S., et al. (2011). Nuclease modulates biofilm formation in community-associated methicillin-resistant Staphylococcus aureus. PLoS ONE 6:e26714. doi: 10.1371/journal.pone.0026714
55. Kuroda, M., Ito, R., Tanaka, Y., Yao, M., Matoba, K., Saito, S., et al. (2008). Staphylococcus aureus surface protein SasG contributes to intercellular autoaggregation of Staphylococcus aureus. Biochem. Biophys. Res. Commun. 377, 1102-1106. doi: 10.1016/j.bbrc.2008.10.134
56. Lauderdale, K. J., Malone, C. L., Boles, B. R., Morcuende, J., and Horswill, A. R. (2010). Biofilm dispersal of community-associated methicillin-resistant Staphylococcus aureus on orthopedic implant material. J. Orthop. Res. 28, 55-61. doi: 10.1002/jor.20943
57. Liu, X., Hu, Y., Pai, P. J., Chen, D., and Lam, H. (2014). Label-free quantitative proteomics analysis of antibiotic response in Staphylococcus aureus to oxacillin. J. Proteome Res. 13, 1223-1233. doi: 10.1021/pr400669d
58. Mack, D., Nedelmann, M., Krokotsch, A., Schwarzkopf, A., Heesemann, J., and Laufs, R. (1994). Characterization of transposon mutants of biofilm-producing Staphylococcus epidermidis impaired in the accumulative phase of biofilm production: genetic identification of a hexosamine-containing polysaccharide intercellular adhesin. Infect. Immun. 62, 3244-3253.
59. Marti, M., Trotonda, M. P., Tormo-Mas, M. A., Vergara-Irigaray, M., Cheung, A. L., Lasa, I., et al. (2010). Extracellular proteases inhibit protein-dependent biofilm formation in Staphylococcus aureus. Microbes Infect. 12, 55-64. doi: 10.1016/j.micinf.2009.10.005
60. Mazmanian, S. K., Liu, G., Jensen, E. R., Lenoy, E., and Schneewind, O. (2000). Staphylococcus aureus sortase mutants defective in the display of surface proteins and in the pathogenesis of animal infections. Proc. Natl. Acad. Sci. U.S.A. 97, 5510-5515. doi: 10.1073/pnas.080520697
61. Mazmanian, S. K., Ton-That, H., and Schneewind, O. (2001). Sortase-catalysed anchoring of surface proteins to the cell wall of Staphylococcus aureus. Mol. Microbiol. 40, 1049-1057. doi: 10.1046/j.1365-2958.2001.02411.x
62. McCourt, J., O'Halloran, D. P., McCarthy, H., O'Gara, J. P., and Geoghegan, J. A. (2014). Fibronectin-binding proteins are required for biofilm formation by community-associated methicillin-resistant Staphylococcus aureus strain LAC. FEMS Microbiol. Lett. 353, 157-164. doi: 10.1111/1574-6968.12424
63. Meenan, N. A., Visai, L., Valtulina, V., Schwarz-linek, U., Norris, N. C., Gurusiddappa, S., et al. (2007). The tandem beta-zipper model defines high affinity fibronectin-binding repeats within Staphylococcus aureus FnBPA. J. Biol. Chem. 282, 25893-25902. doi: 10.1074/jbc.M703063200
64. Mempel, M., Feucht, H., Ziebuhr, W., Endres, M., Laufs, R., and Gruter, L. (1994). Lack of mecA transcription in slime-negative phase variants of methicillin-resistant Staphylococcus epidermidis. Antimicrob. Agents Chemother. 38, 1251-1255. doi: 10.1128/AAC.38.6.1251
65. Mempel, M., Müller, E., Hoffmann, R., Feucht, H., Laufs, R., and Grüter, L. (1995). Variable degree of slime production is linked to different levels of beta-lactam susceptibility in Staphylococcus epidermidis phase variants. Med. Microbiol. Immunol. 184, 109-113. doi: 10.1007/BF00224346
66. Merino, N., Toledo-Arana, A., Vergara-Irigaray, M., Valle, J., Solano, C., Calvo, E., et al. (2009). Protein A-mediated multicellular behavior in Staphylococcus aureus. J. Bacteriol. 191, 832-843. doi: 10.1128/JB.01222-08
67. Mizobuchi, S., Minami, J., Jin, F., Matsushita, O., and Okabe, A. (1994). Comparison of the virulence of methicillin-resistant and methicillin-sensitive Staphylococcus aureus. Microbiol. Immunol. 38, 599-605. doi: 10.1111/j.1348- 0421.1994.tb01829.x
68. Mwangi, M. M., Kim, C., Chung, M., Tsai, J., Vijayadamodar, G., Benitez, M., et al. (2013). Whole-genome sequencing reveals a link between beta-lactam resistance and synthetases of the alarmone (p)ppGpp in Staphylococcus aureus. Microb. Drug Resist. 19, 153-159. doi: 10.1089/mdr.2013.0053
69. Nethercott, C., Mabbett, A. N., Totsika, M., Peters, P., Ortiz, J. C., Nimmo, G. R., et al. (2013). Molecular characterization of endocarditisassociated Staphylococcus aureus. J. Clin. Microbiol. 51, 2131-2138. doi: 10.1128/JCM.00651-13
70. Novick, R. P., Ross, H. F., Projan, S. J., Kornblum, J., Kreiswirth, B., and Moghazeh, S. (1993). Synthesis of staphylococcal virulence factors is controlled by a regulatory RNA molecule. EMBO J. 12, 3967-3975.
71. O'Gara, J. P. (2007). ica and beyond: biofilm mechanisms and regulation in Staphylococcus epidermidis and Staphylococcus aureus. FEMS Microbiol. Lett. 270, 179-188. doi: 10.1111/j.1574-6968.2007.00688.x
72. O'Gara, J. P., and Humphreys, H. (2001). Staphylococcus epidermidis biofilms: importance and implications. J. Med. Microbiol. 50, 582-587.
73. O'Neill, E., Pozzi, C., Houston, P., Humphreys, H., Robinson, D. A., Loughman, A., et al. (2008). A novel Staphylococcus aureus biofilm phenotype mediated by the fibronectin-binding proteins, FnBPA and FnBPB. J. Bacteriol. 190, 3835-3850. doi: 10.1128/JB.00167-08
74. O'Neill, E., Pozzi, C., Houston, P., Smyth, D., Humphreys, H., Robinson, D. A., et al. (2007). Association between methicillin susceptibility and biofilm regulation in Staphylococcus aureus isolates from device-related infections. J. Clin. Microbiol. 45, 1379-1388. doi: 10.1128/JCM.02280-06
75. Oshida, T., Sugai, M., Komatsuzawa, H., Hong, Y. M., Suginaka, H., and Tomasz, A. (1995). A Staphylococcus aureus autolysin that has an N-acetylmuramoyl-Lalanine amidase domain and an endo-beta-N-acetylglucosaminidase domain: cloning, sequence analysis, and characterization. Proc. Natl. Acad. Sci. U.S.A. 92, 285-289. doi: 10.1073/pnas.92.1.28
76. Otto, M. (2013). Coagulase-negative staphylococci as reservoirs of genes facilitating MRSA infection: staphylococcal commensal species such as Staphylococcus epidermidis are being recognized as important sources of genes promoting MRSA colonization and virulence. Bioessays 35, 4-11. doi: 10.1002/bies.201200112
77. Periasamy, S., Joo, H. S., Duong, A. C., Bach, T. H., Tan, V. Y., Chatterjee, S. S., et al. (2012). How Staphylococcus aureus biofilms develop their characteristic structure. Proc. Natl. Acad. Sci. U.S.A. 109, 1281-1286. doi: 10.1073/pnas.1115006109
78. Pozzi, C., Waters, E. M., Rudkin, J. K., Schaeffer, C. R., Lohan, A. J., Tong, P., et al. (2012). Methicillin resistance alters the biofilm phenotype and attenuates virulence in Staphylococcus aureus device-associated infections. PLoS Pathog. 8:e1002626. doi: 10.1371/journal.ppat.1002626
79. Qin, Z., Ou, Y., Yang, L., Zhu, Y., Tolker-Nielsen, T., Molin, S., et al. (2007). Role of autolysin-mediated DNA release in biofilm formation of Staphylococcus epidermidis. Microbiology 153, 2083-2092. doi: 10.1099/mic.0.2007/006031-0
80. Queck, S. Y., Khan, B. A., Wang, R., Bach, T. H., Kretschmer, D., Chen, L., et al. (2009). Mobile genetic element-encoded cytolysin connects virulence to methicillin resistance in MRSA. PLoS Pathog. 5:e1000533. doi: 10.1371/journal. ppat.1000533
81. Rao, F., See, R. Y., Zhang, D., Toh, D. C., Ji, Q., and Liang, Z. X. (2010). YybT is a signaling protein that contains a cyclic dinucleotide phosphodiesterase domain and a GGDEF domain with ATPase activity. J. Biol. Chem. 285, 473-482. doi: 10.1074/jbc.M109.040238
82. Regassa, L. B., Novick, R. P., and Betley, M. J. (1992). Glucose and nonmaintained pH decrease expression of the accessory gene regulator (agr) in Staphylococcus aureus. Infect. Immun. 60, 3381-3388.
83. Rohde, H., Burdelski, C., Bartscht, K., Hussain, M., Buck, F., Horstkotte, M. A., et al. (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. doi: 10.1111/j.1365- 2958.2005.04515.x
84. Rohde, H., Frankenberger, S., Zahringer, U., and Mack, D. (2010). Structure, function and contribution of polysaccharide intercellular adhesin (PIA) to Staphylococcus epidermidis biofilm formation and pathogenesis of biomaterial-associated infections. Eur. J. Cell Biol. 89, 103-111. doi: 10.1016/j.ejcb.2009.10.005
85. Rohde, H., Knobloch, J. K., Horstkotte, M. A., and Mack, D. (2001). Correlation of Staphylococcus aureus icaADBC genotype and biofilm expression phenotype. J. Clin. Microbiol. 39, 4595-4596. doi: 10.1128/JCM.39.12.4595-4596.2001
86. Rudkin, J. K., Edwards, A. M., Bowden, M. G., Brown, E. L., Pozzi, C., Waters, E. M., et al. (2012). Methicillin resistance reduces the virulence of healthcareassociated methicillin-resistant Staphylococcus aureus by interfering with the agr quorum sensing system. J. Infect. Dis. 205, 798-806. doi: 10.1093/infdis/jir845
87. Rudkin, J. K., Laabei, M., Edwards, A. M., Joo, H. S., Otto, M., Lennon, K. L., et al. (2014). Oxacillin alters the toxin expression profile of community-associated methicillin-resistant Staphylococcus aureus. Antimicrob. Agents Chemother. 58, 1100-1107. doi: 10.1128/AAC.01618-13
88. Rupp, M. E., Fey, P. D., Heilmann, C., and 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. doi: 10.1086/319279
89. Schaeffer, C. R., Woods, K. M., Longo, G. M., Kiedrowski, M. R., Paharik, A. E., Büttner, H., et al. (2015). Accumulation-associated protein (Aap) enhances Staphylococcus epidermidis biofilm formation under dynamic conditions and is required for infection in a rat catheter model. Infect. Immun. 83, 214-226. doi: 10.1128/IAI.02177-14
90. Schroeder, K., Jularic, M., Horsburgh, S. M., Hirschhausen, N., Neumann, C., Bertling, A., et al. (2009). Molecular characterization of a novel Staphylococcus aureus surface protein (SasC) involved in cell aggregation and biofilm accumulation. PLoS ONE 4:e7567. doi: 10.1371/journal.pone.0007567
91. Schwarz-Linek, U., Werner, J. M., Pickford, A. R., Gurusiddappa, S., Kim, J. H., Pilka, E. S., et al. (2003). Pathogenic bacteria attach to human fibronectin through a tandem beta-zipper. Nature 423, 177-181. doi: 10.1038/nature01589
92. Shahrooei, M., Hira, V., Stijlemans, B., Merckx, R., Hermans, P. W., and Van eldere, J. (2009). Inhibition of Staphylococcus epidermidis biofilm formation by rabbit polyclonal antibodies against the SesC protein. Infect. Immun. 77, 3670-3678. doi: 10.1128/IAI.01464-08
93. Shanks, R. M., Meehl, M. A., Brothers, K. M., Martinez, R. M., Donegan, N. P., Graber, M. L., et al. (2008). Genetic evidence for an alternative citratedependent biofilm formation pathway in Staphylococcus aureus that is dependent on fibronectin binding proteins and the GraRS two-component regulatory system. Infect. Immun. 76, 2469-2477. doi: 10.1128/IAI.01370-07
94. Shaw, L., Golonka, E., Potempa, J., and Foster, S. J. (2004). The role and regulation of the extracellular proteases of Staphylococcus aureus. Microbiology 150, 217-228. doi: 10.1099/mic.0.26634-0
95. Sung, J. M., Lloyd, D. H., and Lindsay, J. A. (2008). Staphylococcus aureus host specificity: comparative genomics of human versus animal isolates by multi-strain microarray. Microbiology 154, 1949-1959. doi: 10.1099/mic.0.2007/015289-0
96. Sureka, K., Choi, P. H., Precit, M., Delince, M., Pensinger, D. A., Huynh, T. N., et al. (2014). The cyclic dinucleotide c-di-AMP is an allosteric regulator of metabolic enzyme function. Cell 158, 1389-1401. doi: 10.1016/j.cell.2014.07.046
97. Ton-That, H., Mazmanian, S. K., Faull, K. F., and Schneewind, O. (2000). Anchoring of surface proteins to the cell wall of Staphylococcus aureus. Sortase catalyzed in vitro transpeptidation reaction using LPXTG peptide and NH(2)-Gly(3) substrates. J. Biol. Chem. 275, 9876-9881. doi: 10.1074/jbc.275. 13.9876
98. Tormo, M. A., Knecht, E., Götz, F., Lasa, I., and Penadés, J. R. (2005). Bap-dependent biofilm formation by pathogenic species of Staphylococcus: evidence of horizontal gene transfer? Microbiology 151, 2465-2475. doi: 10.1099/mic.0.27865-0
99. Valle, J., Toledo-Arana, A., Berasain, C., Ghigo, J. M., Amorena, B., Penades, J. R., et al. (2003). SarA and not sigmaB is essential for biofilm development by Staphylococcus aureus. Mol. Microbiol. 48, 1075-1087. doi: 10.1046/j.1365- 2958.2003.03493.x
100. Vergara-Irigaray, M., Valle, J., Merino, N., Latasa, C., Garcia, B., Ruiz de los Mozos, I., et al. (2009). Relevant role of fibronectin-binding proteins in Staphylococcus aureus biofilm-associated foreign-body infections. Infect. Immun. 77, 3978-3991. doi: 10.1128/IAI.00616-09
101. Vuong, C., Gerke, C., Somerville, G. A., Fischer, E. R., and Otto, M. (2003). Quorum-sensing control of biofilm factors in Staphylococcus epidermidis. J. Infect. Dis. 188, 706-718. doi: 10.1086/377239
102. Vuong, C., Kocianova, S., Yao, Y., Carmody, A. B., and Otto, M. (2004). Increased colonization of indwelling medical devices by quorum-sensing mutants of Staphylococcus epidermidis in vivo. J. Infect. Dis. 190, 1498-1505. doi: 10.1086/424487
103. Vuong, C., and Otto, M. (2002). Staphylococcus epidermidis infections. Microbes Infect. 4, 481-489. doi: 10.1016/S1286-4579(02)01563-0
104. Vuong, C., Saenz, H. L., Götz, F., and Otto, M. (2000). Impact of the agr quorumsensing system on adherence to polystyrene in Staphylococcus aureus. J. Infect. Dis. 182, 1688-1693. doi: 10.1086/317606
105. Wang, R., Khan, B. A., Cheung, G. Y., Bach, T. H., Jameson-Lee, M., Kong, K. F., et al. (2011). Staphylococcus epidermidis surfactant peptides promote biofilm maturation and dissemination of biofilm-associated infection in mice. J. Clin. Invest. 121, 238-248. doi: 10.1172/JCI42520
106. Wecke, J., Lahav, M., Ginsburg, I., Kwa, E., and Giesbrecht, P. (1986). Inhibition of wall autolysis of staphylococci by sodium polyanethole sulfonate "liquoid." Arch. Microbiol. 144, 110-115. doi: 10.1007/BF00414719
107. Wehrhahn, M. C., Robinson, J. O., Pascoe, E. M., Coombs, G. W., Pearson, J. C., O'Brien, F. G., et al. (2012). Illness severity in community-onset invasive Staphylococcus aureus infection and the presence of virulence genes. J. Infect. Dis. 205, 1840-1848. doi: 10.1093/infdis/jis279
108. Yabu, K., and Kaneda, S. (1995). Salt-induced cell lysis of Staphylococcus aureus. Curr. Microbiol. 30, 299-303. doi: 10.1007/BF00295505
109. Yamada, S., Sugai, M., Komatsuzawa, H., Nakashima, S., Oshida, T., Matsumoto, A., et al. (1996). An autolysin ring associated with cell separation of Staphylococcus aureus. J. Bacteriol. 178, 1565-1571.