Human anti-alpha-hemolysin scFvs mitigate toxin-mediated damage in a mouse model of MRSA pneumonia

Methicillin-resistant Staphylococcus aureus (MRSA) pneumonia represents a serious and potentially fatal infectious complication, hallmarked by its considerable strain on healthcare infrastructure and well-documented association with elevated morbidity and mortality. The clinical burden is particularly pronounced among immunosuppressed individuals and hospitalized patients reliant on mechanical ventilation. Suboptimal therapeutic outcomes associated with conventional antibiotic treatment of MRSA infections have necessitated alternative therapeutic strategies targeting bacterial virulence factors. Among these, alpha-hemolysin has emerged as a critical determinant in the pathogenesis of MRSA-associated pneumonia, representing a promising therapeutic target. Our previous investigation revealed the remarkable neutralizing capabilities of two human single-chain variable fragments (scFvs), designated SP192 and SP220, which effectively target alpha-hemolysin in vitro. To delve deeper into their therapeutic potential in vivo, we administered SP192, SP220, or a combination of the two scFvs to immunocompromised mice with MRSA pneumonia, every 12 h for 72 h. The findings were significant, indicating a marked increase in survival rates among SP192- and SP220-treated mice, with outcomes similar to those observed in the vancomycin-treated control group. Furthermore, both SP192 and SP220, whether administered individually or in combination, significantly reduced bacterial load and mitigated renal and pulmonary damage compared with control groups that received normal saline or an unrelated scFv. These findings highlight the potential of targeted therapies to address a critical need in the management of MRSA pneumonia, which is relevant for clinicians seeking new treatment options. KEY POINTS: • The efficacy of two anti-alpha-hemolysin scFvs was assessed in vivo. • The SP192 and SP220 scFvs improve survival rates and reduce tissue damage. • The combination of SP192 and SP220 has demonstrated the most effective treatment.