Methicillin Resistance Alters the Biofilm Phenotype and Attenuates Virulence in Staphylococcus aureus Device-Associated Infections

PLoS Pathogens

Justine K. Rudkin¹  Pin Tong²  Gerald B. Pier³  Brendan J. Loftus⁴  Amanda J. Lohan⁵  Elaine M. Waters⁵  Ruth C. Massey⁵  James P. O'Gara⁶  Paul D. Fey⁶  Carolyn R. Schaeffer⁶  Clarissa Pozzi⁶ 

[1] Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America;Department of Biology and Biochemistry, University of Bath, Bath, United Kingdom;Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska, United States of America;Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska, United States of America;UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland;UCD School of Biomolecular and Biomedical Science, University College Dublin, Dublin, Ireland

关键词: Biofilms;    Bacterial biofilms;    Methicillin-resistant Staphylococcus aureus;    Phenotypes;    Proteases;    Glucose;    Methicillin resistance;    Mouse models;   

DOI  :  10.1371/journal.ppat.1002626

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY