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

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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.

Oxacillin Kills Vancomycin-Resistant Staphylococcus aureus (VRSA) When Combined with the FtsZ Inhibitor TXA707

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Acknowledgements

This study was supported by NIH grant R01 AI118874. We are indebted to Chia Y. Lee (University of Arkansas for Medical Sciences, Little Rock, AK) and Alexander R. Horswill (University of Colorado School of Medicine, Aurora, CO) for providing us with MSSA RN4220 and MRSA LAC, respectively.

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Authors and Affiliations

  1. Department of Pharmacology, Rutgers Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, NJ, 08854, USA

    Malvika Kaul, Edgar Ferrer-González & Daniel S. Pilch

  2. TAXIS Pharmaceuticals, Inc., 9 Deer Park Drive, Suite J-15, Monmouth Junction, NJ, 08852, USA

    Lilly Mark & Ajit K. Parhi

  3. Department of Medicinal Chemistry, Ernest Mario School of Pharmacy, Rutgers University, 160 Frelinghuysen Road, Piscataway, NJ, 08854, USA

    Edmond J. LaVoie

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  1. Malvika Kaul
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Correspondence to Daniel S. Pilch.

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Drs. Pilch and LaVoie are co-founders of TAXIS Pharmaceuticals and therefore have a financial interest in the company.

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Kaul, M., Ferrer-González, E., Mark, L. et al. Combination with a FtsZ inhibitor potentiates the in vivo efficacy of oxacillin against methicillin-resistant Staphylococcus aureus. Med Chem Res 31, 1705–1715 (2022). https://doi.org/10.1007/s00044-022-02960-5

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