Skip to main content Accessibility help
Hostname: page-component-56f9d74cfd-5k9ck Total loading time: 0.711 Render date: 2022-06-27T16:05:44.901Z Has data issue: true Feature Flags: { "shouldUseShareProductTool": true, "shouldUseHypothesis": true, "isUnsiloEnabled": true, "useRatesEcommerce": false, "useNewApi": true }

9 - Quorum-sensing-dependent regulation of staphylococcal virulence and biofilm development

Published online by Cambridge University Press:  08 August 2009

Jeremy M. Yarwood
Department of Microbiology Carver College of Medicine, University of Iowa, IA USA
Donald R. Demuth
University of Louisville, Kentucky
Richard Lamont
University of Florida
Get access



Staphylococci are a genus of bacteria remarkably adept at causing a variety of human and animal diseases. These range from relatively benign skin infections, such as impetigo, to much more serious ones, including endocarditis, osteomyelitis, toxic shock syndrome, and those associated with implanted medical devices. In fact, the staphylococci are a leading cause of nosocomial infections worldwide, and the continuing emergence of highly drug-resistant strains has created an immediate need for the development of new antimicrobial therapies and strategies. Since the identification of the accessory gene regulator (Agr) quorum sensing system in Staphylococcus aureus, and subsequently in other staphylococcal species, it has been assigned a central role in the regulation of staphylococcal virulence. As such, it has attracted substantial attention as a potential target for controlling staphylococcal disease.

Although recent studies have shown that virulence-gene regulation by Agr is considerably more complex in vivo than initially understood from studies in vitro, it remains clear that expression of Agr, or even lack thereof, is an important determinant in staphylococcal disease development. agr mutants have been shown to be attenuated for virulence in some animal models of infection, including a murine arthritis model, an osteomyelitis model, and a skin abscess model (reviewed in (34)). It has also been shown that expression of Agr, and of Agr-regulated exotoxins, facilitates escape of S. aureus internalized by epithelial cells (49).

Bacterial Cell-to-Cell Communication
Role in Virulence and Pathogenesis
, pp. 199 - 232
Publisher: Cambridge University Press
Print publication year: 2006

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)


Balaban, N., Goldkorn, T., Nhan, R. al. 1998. Autoinducer of virulence as a target for vaccine and therapy against Staphylococcus aureus. Science 280: 438–40.CrossRefGoogle ScholarPubMed
Benito, Y., Kolb, F. A., Romby, al. 2000. Probing the structure of RNAIII, the Staphylococcus aureus agr regulatory RNA, and identification of the RNA domain involved in repression of protein A expression. RNA 6: 668–79.CrossRefGoogle ScholarPubMed
Bischoff, M., Dunman, P., Kormanec, J., et al. 2004. Microarray-based analysis of the Staphylococcus aureus σB regulon. J. Bacteriol. 186: 4085–99.CrossRefGoogle ScholarPubMed
Bischoff, M., Entenza, J. M. and Giachino, P. 2001. Influence of a functional sigB operon on the global regulators sar and agr in Staphylococcus aureus. J. Bacteriol. 183: 5171–9.CrossRefGoogle ScholarPubMed
Cheung, A. L. and Zhang, G. 2002. Global regulation of virulence determinants in Staphylococcus aureus by the SarA protein family. Front. Biosci. 7: 1825–42.CrossRefGoogle ScholarPubMed
Chien, Y., Manna, A. C., Projan, S. J. and Cheung, A. L. 1999. SarA, a global regulator of virulence determinants in Staphylococcus aureus, binds to a conserved motif essential for sar-dependent gene regulation. J. Biol. Chem. 274: 37169–76.CrossRefGoogle ScholarPubMed
Dell'Acqua, G., Giacometti, A., Cirioni, al. 2004. Suppression of drug-resistant staphylococcal infections by the quorum-sensing inhibitor RNAIII-inhibiting peptide. J. Infect. Dis. 190: 318–20.CrossRefGoogle ScholarPubMed
Donlan, R. M. and Costerton, J. W. 2002. Biofilms: survival mechanisms of clinically relevant microorganisms. Clin. Microbiol. Rev. 15: 167–93.CrossRefGoogle ScholarPubMed
Donvito, B., Etienne, J., Denoroy, al. 1997. Synergistic hemolytic activity of Staphylococcus lugdunensis is mediated by three peptides encoded by a non-agr genetic locus. Infect. Immun. 65: 95–100.Google ScholarPubMed
Dufour, P., Jarraud, S., Vandenesch, al. 2002. High genetic variability of the agr locus in Staphylococcus species. J. Bacteriol. 184: 1180–6.CrossRefGoogle ScholarPubMed
Dunman, P. M., Murphy, E., Haney, al. 2001. Transcription profiling-based identification of Staphylococcus aureus genes regulated by the agr and/or sarA loci. J. Bacteriol. 183: 7341–53.CrossRefGoogle ScholarPubMed
Fischetti, V. A., Novick, R. P., Ferretti, J. J., Portnoy, D. A. and Rood, E. J. I. 2000. Gram-Positive Pathogens. Washington, DC: ASM Press.Google Scholar
Fournier, B., Aras, R. and Hooper, D. C. 2000. Expression of the multidrug resistance transporter NorA from Staphylococcus aureus is modified by a two-component regulatory system. J. Bacteriol. 182: 664–71.CrossRefGoogle ScholarPubMed
Fournier, B., Klier, A. and Rapoport, G. 2001. The two-component system ArlS-ArlR is a regulator of virulence gene expression in Staphylococcus aureus. Mol. Microbiol. 41: 247–61.CrossRefGoogle ScholarPubMed
Fowler, V. G. Jr., Sakoulas, G., McIntyre, L. al. 2004. Persistent bacteremia due to methicillin-resistant Staphylococcus aureus infection is associated with agr dysfunction and low-level in vitro resistance to thrombin-induced platelet microbiocidal protein. J. Infect. Dis. 190: 1140–9.CrossRefGoogle Scholar
Frees, D., Qazi, S. N., Hill, P. J. and Ingmer, H. 2003. Alternative roles of ClpX and ClpP in Staphylococcus aureus stress tolerance and virulence. Mol. Microbiol. 48: 1565–78.CrossRefGoogle ScholarPubMed
Gilot, P. and Leeuwen, W. 2004. Comparative analysis of agr locus diversification and overall genetic variability among bovine and human Staphylococcus aureus isolates. J. Clin. Microbiol. 42: 1265–9.CrossRefGoogle ScholarPubMed
Giraudo, A. T., Calzolari, A., Cataldi, A. A., Bogni, C. and Nagel, R. 1999. The sae locus of Staphylococcus aureus encodes a two-component regulatory system. FEMS Microbiol. Lett. 177: 15–22.CrossRefGoogle ScholarPubMed
Giraudo, A. T., Cheung, A. L. and Nagel, R. 1997. The sae locus of Staphylococcus aureus controls exoprotein synthesis at the transcriptional level. Arch. Microbiol. 168: 53–8.CrossRefGoogle ScholarPubMed
Goerke, C., Campana, S., Bayer, M. al. 2000. Direct quantitative transcript analysis of the agr regulon of Staphylococcus aureus during human infection in comparison to the expression profile in vitro. Infect. Immun. 68: 1304–11.CrossRefGoogle ScholarPubMed
Goerke, C., Fluckiger, U., Steinhuber, A., Zimmerli, W. and Wolz, C. 2001. Impact of the regulatory loci agr, sarA and sae of Staphylococcus aureus on the induction of alpha-toxin during device-related infection resolved by direct quantitative transcript analysis. Mol. Microbiol. 40: 1439–47.CrossRefGoogle ScholarPubMed
Goerke, C., Kummel, M., Dietz, K. and Wolz, C. 2003. Evaluation of intraspecies interference due to agr polymorphism in Staphylococcus aureus during infection and colonization. J. Infect. Dis. 188: 250–6.CrossRefGoogle ScholarPubMed
Horsburgh, M. J., Aish, J. L., White, I. al. 2002. σB modulates virulence determinant expression and stress resistance: characterization of a functional rsbU strain derived from Staphylococcus aureus 8325–4. J. Bacteriol. 184: 5457–67.CrossRefGoogle ScholarPubMed
Jarraud, S., Mougel, C., Thioulouse, al. 2002. Relationships between Staphylococcus aureus genetic background, virulence factors, agr groups (alleles), and human disease. Infect. Immun. 70: 631–41.CrossRefGoogle Scholar
Ji, G., Beavis, R. and Novick, R. P. 1997. Bacterial interference caused by autoinducing peptide variants. Science 276: 2027–30.CrossRefGoogle ScholarPubMed
Kahl, B. C., Becker, K., Friedrich, A. al. 2003. agr-dependent bacterial interference has no impact on long-term colonization of Staphylococcus aureus during persistent airway infection of cystic fibrosis patients. J. Clin. Microbiol. 41: 5199–201.CrossRefGoogle ScholarPubMed
Kies, S., Vuong, C., Hille, al. 2003. Control of antimicrobial peptide synthesis by the agr quorum sensing system in Staphylococcus epidermidis: activity of the antibiotic epidermin is regulated at the level of precursor peptide processing. Peptides 24: 329–38.CrossRefGoogle ScholarPubMed
Li, M., Guan, M., Jiang, X. al. 2004. Genetic polymorphism of the accessory gene regulator (agr) locus in Staphylococcus epidermidis and its association with pathogenicity. J. Med. Microbiol. 53: 545–9.CrossRefGoogle ScholarPubMed
Li, S., Arvidson, S. and Mollby, R. 1997. Variation in the agr-dependent expression of alpha-toxin and protein A among clinical isolates of Staphylococcus aureus from patients with septicaemia. FEMS Microbiol. Lett. 152: 155–61.CrossRefGoogle ScholarPubMed
Lina, G., Boutite, F., Tristan, al. 2003. Bacterial competition for human nasal cavity colonization: role of staphylococcal agr alleles. Appl. Environ. Microbiol. 69: 18–23.CrossRefGoogle ScholarPubMed
Mayville, P., Ji, G., Beavis, al. 1999. Structure-activity analysis of synthetic autoinducing thiolactone peptides from Staphylococcus aureus responsible for virulence. Proc. Natn. Acad. Sci. USA 96: 1218–23.CrossRefGoogle ScholarPubMed
McNamara, P. J., Milligan-Monroe, K. C., Khalili, S. and Proctor, R. A. 2000. Identification, cloning, and initial characterization of rot, a locus encoding a regulator of virulence factor expression in Staphylococcus aureus. J. Bacteriol. 182: 3197–203.CrossRefGoogle ScholarPubMed
Moise-Broder, P. A., Sakoulas, G., Eliopoulos, G. al. 2004. Accessory gene regulator group II polymorphism in methicillin-resistant Staphylococcus aureus is predictive of failure of vancomycin therapy. Clin. Infect. Dis. 38: 1700–5.CrossRefGoogle ScholarPubMed
Novick, R. P. 2003. Autoinduction and signal transduction in the regulation of staphylococcal virulence. Mol. Microbiol. 48: 1429–49.CrossRefGoogle ScholarPubMed
Novick, R. P. and Jiang, D. 2003. The staphylococcal saeRS system coordinates environmental signals with agr quorum sensing. Microbiology 149: 2709–17.CrossRefGoogle ScholarPubMed
Novick, R. P., Ross, H. F., Figueiredo, A. M. N. al. 2000. Activation and inhibition of the staphylococcal AGR system. Science 287: 391.CrossRefGoogle Scholar
Novick, R. P., Ross, H. F., Projan, S. al. 1993. Synthesis of staphylococcal virulence factors is controlled by a regulatory RNA molecule. EMBO J. 12: 3967–75.Google ScholarPubMed
Otto, M. 2001. Staphylococcus aureus and Staphylococcus epidermidis peptide pheromones produced by the accessory gene regulator system. Peptides 22: 1603–8.CrossRefGoogle Scholar
Parsek, M. R. and Singh, P. K. 2003. Bacterial biofilms: an emerging link to disease pathogenesis. Annu. Rev. Microbiol. 57: 677–701.CrossRefGoogle ScholarPubMed
Pratten, J., Foster, S. J., Chan, P. F., Wilson, M. and Nair, S. P. 2001. Staphylococcus aureus accessory regulators: expression within biofilms and effect on adhesion. Microbes Infect. 3: 633–7.CrossRefGoogle ScholarPubMed
Projan, S. J. and R. P. Novick 1997. The molecular basis of pathogenicity. In Crossley, K. B. and Archer, G. L. (eds.), The Staphylococci in Human Disease, pp. 55–81. New York: Churchill Livingstone.Google Scholar
Rothfork, J. M., Dessus-Babus, S., Wamel, W. J., Cheung, A. L. and Gresham, H. D. 2003. Fibrinogen depletion attenuates Staphyloccocus aureus infection by preventing density-dependent virulence gene up-regulation. J. Immunol. 171: 5389–95.CrossRefGoogle ScholarPubMed
Said-Salim, B., Dunman, P. M., McAleese, F. al. 2003. Global regulation of Staphylococcus aureus genes by Rot. J. Bacteriol. 185: 610–19.CrossRefGoogle ScholarPubMed
Sakinc, T., Kulczak, P., Henne, K. and Gatermann, S. G. 2004. Cloning of an agr homologue of Staphylococcus saprophyticus. FEMS Microbiol. Lett. 237: 157–61.CrossRefGoogle ScholarPubMed
Sakoulas, G., Eliopoulos, G. M., Moellering, R. C. al. 2002. Accessory gene regulator (agr) locus in geographically diverse Staphylococcus aureus isolates with reduced susceptibility to vancomycin. Antimicrob. Agents Chemother. 46: 1492–502.CrossRefGoogle ScholarPubMed
Schwan, W. R., Langhorne, M. H., Ritchie, H. D. and Stover, C. K. 2003. Loss of hemolysin expression in Staphylococcus aureus agr mutants correlates with selective survival during mixed infections in murine abscesses and wounds. FEMS Immunol. Med. Microbiol. 38: 23–8.CrossRefGoogle ScholarPubMed
Shenkman, B., Rubinstein, E., Cheung, A. al. 2001. Adherence properties of Staphylococcus aureus under static and flow conditions: roles of agr and sar loci, platelets, and plasma ligands. Infect. Immun. 69: 4473–8.CrossRefGoogle ScholarPubMed
Shenkman, B., Varon, D., Tamarin, al. 2002. Role of agr (RNAIII) in Staphylococcus aureus adherence to fibrinogen, fibronectin, platelets and endothelial cells under static and flow conditions. J. Med. Microbiol. 51: 747–54.CrossRefGoogle ScholarPubMed
Shompole, S., Henon, K. T., Liou, L. al. 2003. Biphasic intracellular expression of Staphylococcus aureus virulence factors and evidence for Agr-mediated diffusion sensing. Mol. Microbiol. 49: 919–27.CrossRefGoogle ScholarPubMed
Somerville, G. A., Beres, S. B., Fitzgerald, J. al. 2002. In vitro serial passage of Staphylococcus aureus: changes in physiology, virulence factor production, and agr nucleotide sequence. J. Bacteriol. 184: 1430–7.CrossRefGoogle ScholarPubMed
Tegmark, K., Morfeldt, E. and Arvidson, S. 1998. Regulation of agr-dependent virulence genes in Staphylococcus aureus by RNAIII from coagulase-negative staphylococci. J. Bacteriol. 180: 3181–6.Google ScholarPubMed
Throup, J. P., Zappacosta, F., Lunsford, R. al. 2001. The srhSR gene pair from Staphylococcus aureus: genomic and proteomic approaches to the identification and characterization of gene function. Biochemistry 40: 10392–401.CrossRefGoogle ScholarPubMed
Truong-Bolduc, Q. C., Zhang, X. and Hooper, D. C. 2003. Characterization of NorR protein, a multifunctional regulator of norA expression in Staphylococcus aureus. J. Bacteriol. 185: 3127–38.CrossRefGoogle ScholarPubMed
Tseng, C. W., Zhang, S. and Stewart, G. C. 2004. Accessory gene regulator control of staphylococcal enterotoxin d gene expression. J. Bacteriol. 186: 1793–801.CrossRefGoogle ScholarPubMed
Wamel, W. J., Rossum, G., Verhoef, J., Vandenbroucke-Grauls, C. M. and Fluit, A. C. 1998. Cloning and characterization of an accessory gene regulator (agr)-like locus from Staphylococcus epidermidis. FEMS Microbiol. Lett. 163: 1–9.CrossRefGoogle ScholarPubMed
Vandenesch, F., Kornblum, J. and Novick, R. P. 1991. A temporal signal, independent of agr, is required for hla but not spa transcription in Staphylococcus aureus. J. Bacteriol. 173: 6313–20.CrossRefGoogle Scholar
Vandenesch, F., Projan, S. J., Kreiswirth, B., Etienne, J. and Novick, R. P. 1993. Agr-related sequences in Staphylococcus lugdunensis. FEMS Microbiol. Lett. 111: 115–22.CrossRefGoogle ScholarPubMed
Vuong, C., Durr, M., Carmody, A. al. 2004. Regulated expression of pathogen-associated molecular pattern molecules in Staphylococcus epidermidis: quorum-sensing determines pro-inflammatory capacity and production of phenol-soluble modulins. Cell. Microbiol. 6: 753–9.CrossRefGoogle ScholarPubMed
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: 706–18.CrossRefGoogle ScholarPubMed
Vuong, C., Gotz, F. and Otto, M. 2000. Construction and characterization of an agr deletion mutant of Staphylococcus epidermidis. Infect. Immun. 68: 1048–53.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
Vuong, C., Saenz, H. L., Gotz, F. and Otto, M. 2000. Impact of the agr quorum-sensing system on adherence to polystyrene in Staphylococcus aureus. J. Infect. Dis. 182: 1688–93.CrossRefGoogle ScholarPubMed
Wamel, W. V., Xiong, Y. -Q., Bayer, al. 2002. Regulation of Staphylococcus aureus type 5 capsular polysaccharides by agr and sarA in vitro and in an experimental endocarditis model. Microb. Pathogen. 33: 73–9.CrossRefGoogle Scholar
Wesson, C. A., Liou, L. E., Todd, K. al. 1998. Staphylococcus aureus Agr and Sar global regulators influence internalization and induction of apoptosis. Infect. Immun. 66: 5238–43.Google ScholarPubMed
Xiong, Y. Q., Wamel, W., Nast, C. al. 2002. Activation and transcriptional interaction between agr RNAII and RNAIII in Staphylococcus aureus in vitro and in an experimental endocarditis model. J. Infect. Dis. 186: 668–77.CrossRefGoogle Scholar
Yarwood, J. M. 2004. Quorum sensing in Staphylococcus aureus biofilms. Presented at the 11th International Symposium on Staphylococci and Staphylococcal Infections, Charleston, SC, October 2004.
Yarwood, J. M., Bartels, D. J., Volper, E. M. and Greenberg, E. P. 2004. Quorum sensing in Staphylococcus aureus biofilms. J. Bacteriol. 186: 1838–50.CrossRefGoogle ScholarPubMed
Yarwood, J. M., McCormick, J. K., Paustian, M. L., Kapur, V. and Schlievert, P. M. 2002. Repression of the Staphylococcus aureus accessory gene regulator in serum and in vivo. J. Bacteriol. 184: 1095–101.CrossRefGoogle ScholarPubMed
Yarwood, J. M., McCormick, J. K. and Schlievert, P. M. 2001. Identification of a novel two-component regulatory system that acts in global regulation of virulence factors of Staphylococcus aureus. J. Bacteriol. 183: 1113–23.CrossRefGoogle ScholarPubMed
Cited by

Save book to Kindle

To save this book to your Kindle, first ensure is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about saving to your Kindle.

Note you can select to save to either the or variations. ‘’ emails are free but can only be saved to your device when it is connected to wi-fi. ‘’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

Find out more about the Kindle Personal Document Service.

Available formats

Save book to Dropbox

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Dropbox.

Available formats

Save book to Google Drive

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Google Drive.

Available formats