Redeploying β-Lactam Antibiotics as a Novel Antivirulence Strategy for the Treatment of Methicillin-ResistantStaphylococcus aureusInfections

Abstract

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.

Impaired alanine transport or exposure to D-cycloserine increases the susceptibility of MRSA to β-lactam antibiotics

“…Recovery of growth in media supplemented with oxacillin or cefoxitin alone was evident after 8 h (Fig. 3), reflecting the selection and expansion of HoR mutants as described previously [2, 18, 20]. Recovery of growth in cultures exposed to DCS alone was also evident (Fig.…”

“…This results in significant morbidity and mortality, with up to 20% of patients with systemic methicillin resistant S. aureus (MRSA) infections dying, despite receiving treatment with anti-staphylococcal drugs [1]. As part of our efforts to identify improved therapeutic approaches for MRSA infections, we recently described the novel use of β -lactam antibiotics to attenuate the virulence of MRSA-induced invasive pneumonia and sepsis [2]. We demonstrated that oxacillin-induced repression of the Agr quorum-sensing system and altered cell wall architecture resulted in downregulated toxin production and increased MRSA killing by phagocytic cells, respectively [2].…”

“…As part of our efforts to identify improved therapeutic approaches for MRSA infections, we recently described the novel use of β -lactam antibiotics to attenuate the virulence of MRSA-induced invasive pneumonia and sepsis [2]. We demonstrated that oxacillin-induced repression of the Agr quorum-sensing system and altered cell wall architecture resulted in downregulated toxin production and increased MRSA killing by phagocytic cells, respectively [2]. Supporting this in vitro data, a randomised controlled trial involving 60 patients showed that the β -lactam antibiotic flucloxacillin in combination with vancomycin shortened the duration of MRSA bacteraemia from 3 days to 1.9 days [3, 4].…”

Early Administration of Adjuvant β‐Lactam Therapy in Combination with Vancomycin among Patients with Methicillin‐Resistant Staphylococcus aureus Bloodstream Infection: A Retrospective, Multicenter Analysis

“…Proposed methods of synergy between β‐lactams and vancomycin are summarized elsewhere . In addition, β‐lactams synergize with innate host defense peptides against MRSA and attenuate MRSA virulence . While in vitro and in vivo support for adjuvant β‐lactam therapy for MRSA continues to grow, few studies have examined the impact of empiric adjuvant β‐lactam therapy on clinical outcomes in patients with MRSA bloodstream infection, but the results of these studies are encouraging …”

“…23,24 In addition, b-lactams synergize with innate host defense peptides against MRSA and attenuate MRSA virulence. 25,26 While in vitro and in vivo support for adjuvant b-lactam therapy for MRSA continues to grow, few studies have examined the impact of empiric adjuvant b-lactam therapy on clinical outcomes in patients with MRSA bloodstream infection, but the results of these studies are encouraging. 14,15 MRSA bloodstream infecƟon treated with vancomycin (VAN) n=201 A retrospective, single-center cohort study demonstrated that empiric, adjuvant b-lactam therapy led to an enhanced rate of microbiologic eradication compared to vancomycin alone (96% compared to 80%, respectively; p=0.021).…”