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Nafcillin enhances innate immune-mediated killing of methicillin-resistant Staphylococcus aureus

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Abstract

Based on in vitro synergy studies, the addition of nafcillin to daptomycin was used to treat refractory methicillin-resistant Staphylococcus aureus (MRSA) bacteremia. Daptomycin is a de facto cationic antimicrobial peptide in vivo, with antistaphylococcal mechanisms reminiscent of innate host defense peptides (HDPs). In this study, the effects of nafcillin on HDP activity against MRSA were examined in vitro and in vivo. Exposures to β-lactam antimicrobials in general, and nafcillin in particular, significantly increased killing of S. aureus by selected HDPs from keratinocytes, neutrophils, and platelets. This finding correlated with enhanced killing of MRSA by whole blood, neutrophils, and keratinocytes after growth in nafcillin. Finally, nafcillin pretreatment ex vivo reduced MRSA virulence in a murine subcutaneous infection model. Despite the lack of direct activity against MRSA, these studies show potent, consistent, and generalized nafcillin-mediated “sensitization” to increased killing of MRSA by various components of the innate host response. The use of nafcillin as adjunctive therapy in MRSA bacteremia merits further study and should be considered in cases refractory to standard therapy.

Key messages

  • Nafcillin has been used as adjunctive therapy to clear persistent MRSA bacteremia.

  • Nafcillin enhances killing of MRSA by a cadre of innate host defense peptides.

  • Nafcillin increases binding of human cathelicidin LL-37 to the MRSA membrane.

  • Nafcillin enhances killing of MRSA by neutrophils.

  • Nafcillin reduces virulence of MRSA in a murine subcutaneous infection model.

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Acknowledgments

We thank Anna Salvioni for assistance with peroxide assays. This research was supported by National Institutes of Health grants HD071600 (GS), AI057153 (VN), AI052453 (VN), R01GM073898 (JP), AI39108 (ASB), AI39001 (MRY), and AI48031 (MRY). CYO was supported through the UCSD/SDSU IRACDA Postdoctoral Fellowship Program (GM06852). No funding bodies had any role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Conflicts of interest

GS has received speaking honoraria from Cubist, Forest, and Pfizer Pharmaceuticals, consulting fees from Cubist and Forest Pharmaceuticals, and research grant support from Forest Pharmaceuticals. ASB has current research grants from Cubist Pharmaceuticals and Trius Therapeutics, and has received speaking honoraria from Cubist Pharmaceuticals. MRY is a founder of NovaDigm Therapeutics, Inc., and has participated in research programs supported in part by grants from Cubist Pharmaceuticals. VN was on the Scientific Advisory Board of Trius Therapeutics.

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Authors and Affiliations

  1. Department of Pediatrics, University of California, San Diego, La Jolla, CA, 92093, USA

    George Sakoulas, Cheryl Y. Okumura, Wdee Thienphrapa, Joshua Olson, Quang Dam, Mary E. Hensler & Victor Nizet

  2. Skaggs School of Pharmacy & Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, 92093, USA

    Victor Nizet

  3. Department of Biological Sciences, University of California, San Diego, La Jolla, CA, 92093, USA

    Poochit Nonejuie & Joseph Pogliano

  4. Department of Biology, Occidental College, Los Angeles, CA, 90041, USA

    Cheryl Y. Okumura

  5. Department of Medicine, New York Medical College, Valhalla, NY, 10595, USA

    Abhay Dhand

  6. David Geffen School of Medicine at UCLA and the Los Angeles Biomedical Research Institute at Harbor–UCLA Medical Center, Torrance, CA, 90509, USA

    Michael R. Yeaman & Arnold S. Bayer

  7. Division of Pediatric Pharmacology & Drug Discovery, University of California San Diego School of Medicine, 9500 Gilman Drive, Mail Code 0687, La Jolla, CA, 92093-0687, USA

    George Sakoulas & Victor Nizet

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  1. George Sakoulas
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Sakoulas, G., Okumura, C.Y., Thienphrapa, W. et al. Nafcillin enhances innate immune-mediated killing of methicillin-resistant Staphylococcus aureus . J Mol Med 92, 139–149 (2014). https://doi.org/10.1007/s00109-013-1100-7

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  • DOI: https://doi.org/10.1007/s00109-013-1100-7

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