Combination with a FtsZ inhibitor potentiates the in vivo efficacy of oxacillin against methicillin-resistant Staphylococcus aureus.

Abstract

Oxacillin is a first-line antibiotic for the treatment of methicillin-sensitive Staphylococcus aureus (MSSA) infections but is ineffective against methicillin-resistant S. aureus (MRSA) due to resistance. Here we present results showing that co-administering oxacillin with the FtsZ-targeting prodrug TXA709 renders oxacillin efficacious against MRSA. The combination of oxacillin and the active product of TXA709 (TXA707) is associated with synergistic bactericidal activity against clinical isolates of MRSA that are resistant to current standard-of-care antibiotics. We show that MRSA cells treated with oxacillin in combination with TXA707 exhibit morphological characteristics and PBP2 mislocalization behavior similar to that exhibited by MSSA cells treated with oxacillin alone. Co-administration with TXA709 renders oxacillin efficacious in mouse models of both systemic and tissue infection with MRSA, with this efficacy being observed at human-equivalent doses of oxacillin well below that recommended for daily adult use. Pharmacokinetic evaluations in mice reveal that co-administration with TXA709 also increases total exposure to oxacillin. Viewed as a whole, our results highlight the clinical potential of repurposing oxacillin to treat MRSA infections through combination with a FtsZ inhibitor.