Redeploying β-lactam antibiotics as a novel antivirulence strategy for the treatment of methicillin-resistant Staphylococcus aureus infections

Innovative approaches to the use of existing antibiotics is an important strategy in efforts to address the escalating antimicrobial
resistance crisis. We report a new approach to the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections
by demonstrating that oxacillin can be used to significantly attenuate the virulence of MRSA despite the pathogen being resistant
to this drug. Using mechanistic in vitro assays and in vivo models of invasive pneumonia and sepsis, we show that oxacillin treated MRSA
strains are significantly attenuated in virulence. This effect is based primarily on the oxacillin-dependent repression
of the accessory gene regulator quorum-sensing system and altered cell wall architecture, which in turn lead to increased susceptibility
to host killing of MRSA. Our data indicate that β-lactam antibiotics should be included in the treatment regimen as an
adjunct antivirulence therapy for patients with MRSA infections. This would represent an important change to current clinical
practice for treatment of MRSA infection, with the potential to significantly improve patient outcomes in a safe, cost-effective
manner.
Keywords. MRSA; antibiotic; beta-lactam; virulence; attenuation.