New research led by Dr. Jim O’Gara’s lab has found that, as the superbug Methicillin Resistant Staphylococcus aureus (MRSA) resists antibiotics, it becomes less virulent. These findings were published on April 5th in PLoS Pathogens and highlighted as ‘Featured Research’ in the current edition of the open-access journal.
The research revealed that Staphylococcus aureus (SA) bacterial cells use sugars to stick to each other and to surfaces as biofilms, while MRSA instead use proteins to form biofilms.
With funding from the Irish Health Research Board, the O’ Gara lab brought the project further and looked at the effects of turning SA into MRSA in the lab. They used a preclinical model that introduced infection by allowing the bacteria to form biofilms on implanted medical devices. Their findings suggest that hospital-acquired MRSA may have made adaptations vital for its survival in its hostile environment by sacrificing unnecessary levels of virulence for essential antibiotic resistance.
“What the data show is that if you take SA and you make it resistant to methicillin, you change the way it forms biofilms, but you also make it less virulent in a preclinical model,” explains Dr. O’Gara, whose group worked on the project with colleagues at the University of Bath, Harvard Medical School and the University of Nebraska.
“It’s like the bacteria are making a decision to divert their energy towards becoming resistant to the drugs, and they are not going to expend energy producing as many toxins or enzymes. This trade-off works for the pathogen because patients in hospital, particularly in an intensive care setting, can be very immuno-compromised and the pathogen does not need to be very virulent,” he says. “On the other hand, the bacterium does need to be very antibiotic resistant, due to the necessarily high levels of antibiotic usage in intensive care units.”
Dr. O’Gara is now looking into how the discovery could be used to help make MRSA less nasty for patients who get infected. “It may open up new ways to find anti-virulence drugs,” he says.
Two students from Dr. O’ Gara’s group were primarily engaged in this research: Clarissa Pozzi, who is now at Harvard Medical School and Elaine Waters, still based in Jim's SBBS group.
Link to Dr. Jim O' Gara's research profile, Senior Lecturer in the UCD School of Biomolecular & Biomedical Science
Reference:
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, (2012), Methicillin Resistance Alters the Biofilm Phenotype and Attenuates Virulence in Staphylococcus aureus Device-Associated Infections. PLoS Pathog 8(4):e1002626. doi:10.1371/journal.ppat.1002626
Publication URL:
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.