Methicillin resistance alters the biofilm phenotype and attenuates virulence in staphylococcus aureus device-associated infections

Clarissa Pozzi, Elaine M. Waters, Justine K. Rudkin, Carolyn R. Schaeffer, Amanda J. Lohan, Pin Tong, Brendan J. Loftus, Gerald B. Pier, Paul D Fey, Ruth C. Massey, James P. O'Gara

Research output: Contribution to journalArticle

146 Citations (Scopus)

Abstract

Clinical isolates of Staphylococcus aureus can express biofilm phenotypes promoted by the major cell wall autolysin and the fibronectin-binding proteins or the icaADBC-encoded polysaccharide intercellular adhesin/poly-N-acetylglucosamine (PIA/PNAG). Biofilm production in methicillin-susceptible S. aureus (MSSA) strains is typically dependent on PIA/PNAG whereas methicillin-resistant isolates express an Atl/FnBP-mediated biofilm phenotype suggesting a relationship between susceptibility to β-lactam antibiotics and biofilm. By introducing the methicillin resistance gene mecA into the PNAG-producing laboratory strain 8325-4 we generated a heterogeneously resistant (HeR) strain, from which a homogeneous, high-level resistant (HoR) derivative was isolated following exposure to oxacillin. The HoR phenotype was associated with a R602H substitution in the DHHA1 domain of GdpP, a recently identified c-di-AMP phosphodiesterase with roles in resistance/tolerance to β-lactam antibiotics and cell envelope stress. Transcription of icaADBC and PNAG production were impaired in the 8325-4 HoR derivative, which instead produced a proteinaceous biofilm that was significantly inhibited by antibodies against the mecA-encoded penicillin binding protein 2a (PBP2a). Conversely excision of the SCCmec element in the MRSA strain BH1CC resulted in oxacillin susceptibility and reduced biofilm production, both of which were complemented by mecA alone. Transcriptional activity of the accessory gene regulator locus was also repressed in the 8325-4 HoR strain, which in turn was accompanied by reduced protease production and significantly reduced virulence in a mouse model of device infection. Thus, homogeneous methicillin resistance has the potential to affect agr- and icaADBC-mediated phenotypes, including altered biofilm expression and virulence, which together are consistent with the adaptation of healthcare-associated MRSA strains to the antibiotic-rich hospital environment in which they are frequently responsible for device-related infections in immuno-compromised patients.

Original languageEnglish (US)
Article numbere1002626
JournalPLoS pathogens
Volume8
Issue number4
DOIs
StatePublished - Apr 1 2012

Fingerprint

Methicillin Resistance
Biofilms
Virulence
Staphylococcus aureus
Phenotype
Equipment and Supplies
Infection
Oxacillin
Lactams
Acetylglucosamine
Methicillin-Resistant Staphylococcus aureus
Anti-Bacterial Agents
N-Acetylmuramoyl-L-alanine Amidase
Penicillin-Binding Proteins
Methicillin
Phosphoric Diester Hydrolases
Regulator Genes
Fibronectins
Cell Wall
Carrier Proteins

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Molecular Biology
  • Genetics
  • Virology

Cite this

Pozzi, C., Waters, E. M., Rudkin, J. K., Schaeffer, C. R., Lohan, A. J., Tong, P., ... O'Gara, J. P. (2012). Methicillin resistance alters the biofilm phenotype and attenuates virulence in staphylococcus aureus device-associated infections. PLoS pathogens, 8(4), [e1002626]. https://doi.org/10.1371/journal.ppat.1002626

Methicillin resistance alters the biofilm phenotype and attenuates virulence in staphylococcus aureus device-associated infections. / Pozzi, Clarissa; Waters, Elaine M.; Rudkin, Justine K.; Schaeffer, Carolyn R.; Lohan, Amanda J.; Tong, Pin; Loftus, Brendan J.; Pier, Gerald B.; Fey, Paul D; Massey, Ruth C.; O'Gara, James P.

In: PLoS pathogens, Vol. 8, No. 4, e1002626, 01.04.2012.

Research output: Contribution to journalArticle

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 pathogens, vol. 8, no. 4, e1002626. https://doi.org/10.1371/journal.ppat.1002626
Pozzi, Clarissa ; Waters, Elaine M. ; Rudkin, Justine K. ; Schaeffer, Carolyn R. ; Lohan, Amanda J. ; Tong, Pin ; Loftus, Brendan J. ; Pier, Gerald B. ; Fey, Paul D ; Massey, Ruth C. ; O'Gara, James P. / Methicillin resistance alters the biofilm phenotype and attenuates virulence in staphylococcus aureus device-associated infections. In: PLoS pathogens. 2012 ; Vol. 8, No. 4.
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