PASTI

Prevention of aggregation in treatment of Staphylococcus aureus infections

Background

 

Infections with Staphylococcus aureus are causing life-threatening diseases in hospitals worldwide (1-4). Data from the USA show that about 1% of hospitalized patients acquire infections with S. aureus. Of these, about 10% are fatal resulting in 12,000 deaths and $9.5 billion in excess costs, annually (5, 6). S. aureus has an ability to cause persistent infections, which even for strains that are not multidrug-resistant, can be hard to eradicate with antibiotic therapy.

One reason for persistent infections is S. aureus’ ability to establish itself in sessile densely packed communities known as biofilms on natural body surfaces as well as medical implants (7, 8). In contrast to multidrug-resistant S. aureus strains (MRSA), which can still be treated with some antibiotics (9), all S. aureus strains become highly resistant to antibiotics just by living in biofilms (10). However, cells in a biofilm are per definition sessile and if they detach from the biofilm to spread, they become vulnerable to antibiotics as well as immune defenses (11-13). Some pathogens have circumvented this problem by assembling into large mobile multi-cellular units (aggregates) which opposed to biofilms are not attached to a surface (12, 14-17). In addition to being mobile, aggregates possess the same protective properties as biofilms (12, 17) and has been shown to be essential for adherence to host cells, phagocytosis resistance and virulence in mice (16). Furthermore, aggregation is induced in clinical settings (18, 19) and may thus be a hitherto overlooked condition with serious clinical consequences such as embolism (1-4).

 

Reference List

 

1. Pandey,B.B., Dang,T.C., & Healy,J.F. Embolic stroke complicating Staphylococcus aureus endocarditis circumstantially linked to rectal trauma from foreign body: a first case report. BMC. Infect. Dis. 5, 42 (2005).

2. Tonges,L., Pilgram-Pastor,S., Puls,M., & Schmidt,H. Septic embolic encephalitis after Staphylococcus aureus endocarditis of a prosthetic valve in a 57-year-old woman: a case report. Cases. J. 2, 6653 (2009).

3. Liao,C.H., Yao,T.C., Chung,H.T., Lien,R.I., & Huang,J.L. Staphylococcal endocarditis and multiple emboli in a patient with systemic lupus erythematosus. J. Rheumatol. 31, 2305-2306 (2004).

4. Aslam,A.F., Aslam,A.K., Thakur,A.C., Vasavada,B.C., & Khan,I.A. Staphylococcus aureus infective endocarditis and septic pulmonary embolism after septic abortion. Int. J. Cardiol. 105, 233-235 (2005).

5. Noskin,G.A. et al. The burden of Staphylococcus aureus infections on hospitals in the United States: an analysis of the 2000 and 2001 Nationwide Inpatient Sample Database. Arch. Intern. Med. 165, 1756-1761 (2005).

6. Rubin,R.J. et al. The economic impact of Staphylococcus aureus infection in New York City hospitals. Emerg. Infect. Dis. 5, 9-17 (1999).

7. Otto,M. Staphylococcal biofilms. Curr. Top. Microbiol. Immunol. 322, 207-228 (2008).

8. Brady,R.A., Leid,J.G., Calhoun,J.H., Costerton,J.W., & Shirtliff,M.E. Osteomyelitis and the role of biofilms in chronic infection. FEMS Immunol. Med. Microbiol. 52, 13-22 (2008).

9. Logman,J.F. et al. Comparative effectiveness of antibiotics for the treatment of MRSA complicated skin and soft tissue infections. Curr. Med. Res. Opin. 26, 1565-1578 (2010).

10. del Pozo,J.L. & Patel,R. The challenge of treating biofilm-associated bacterial infections. Clin. Pharmacol. Ther. 82, 204-209 (2007).

11. Kharazmi,A. Mechanisms involved in the evasion of the host defence by Pseudomonas aeruginosa. Immunol. Lett. 30, 201-205 (1991).

12. Alhede,M. et al. Phenotypes of Non-Attached Pseudomonas aeruginosa Aggregates Resemble Surface Attached Biofilm. PLoS One. 6, e27943 (2011).

13. Jensen,E.T., Kharazmi,A., Hoiby,N., & Costerton,J.W. Some bacterial parameters influencing the neutrophil oxidative burst response to Pseudomonas aeruginosa biofilms. APMIS 100, 727-733 (1992).

14. Schleheck,D. et al. Pseudomonas aeruginosa PAO1 preferentially grows as aggregates in liquid batch cultures and disperses upon starvation. PLoS. ONE. 4, e5513 (2009).

15. Andersen,M.T. et al. Diverse roles for HspR in Campylobacter jejuni revealed by the proteome, transcriptome and phenotypic characterization of an hspR mutant. Microbiology 151, 905-915 (2005).

16. Frick,I.M., Morgelin,M., & Bjorck,L. Virulent aggregates of Streptococcus pyogenes are generated by homophilic protein-protein interactions. Mol. Microbiol. 37, 1232-1247 (2000).

17. Haaber,J., Cohn,M.T., Frees,D., Andersen,T.J., & Ingmer,H. Planktonic Aggregates of Staphylococcus aureus Protect against Common Antibiotics. PLoS. ONE. 7, e41075 (2012).

18. Kapral,F.A. Clumping of Staphylococcus aureus in the peritoneal cavity of mice. J. Bacteriol. 92, 1188-1195 (1966).

19. Fluckiger,U. et al. Biofilm formation, icaADBC transcription, and polysaccharide intercellular adhesin synthesis by staphylococci in a device-related infection model. Infect. Immun. 73, 1811-1819 (2005).

 

Contact PASTI: Jakob Haaber - Dep.Veterinary Disease Biology - University of Copenhagen - Stigboejlen 4 - 1870 Frederiksberg C - jhaa@sund.ku.dk