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Combination therapy with iron chelation and vancomycin in treating murine staphylococcemia
G Luo1, B Spellberg, T Gebremariam
1Division of Infectious Diseases, Los Angeles Biomedical Research Institute, Harbor-University of California Los Angeles (UCLA) Medical Center, 1124 West Carson St., St. John's Cardiovascular Research Center, Torrance, CA, 90502, USA.
Summary
Deferasirox (Def) combined with vancomycin (Van) effectively kills methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-intermediate S. aureus (VISA) in vitro and in mice. This combination enhances vancomycin
Area of Science:
- Microbiology
- Infectious Diseases
- Pharmacology
Background:
- Iron acquisition is a critical virulence factor for Staphylococcus aureus.
- Antibiotic resistance in S. aureus, particularly MRSA and VISA strains, necessitates novel therapeutic strategies.
- Iron chelators are being explored as potential adjunctive treatments for bacterial infections.
Purpose of the Study:
- To evaluate the efficacy of deferasirox (Def), an iron chelator, alone and in combination with vancomycin (Van) against MRSA and VISA strains.
- To investigate the mechanism by which Def might enhance Van's activity, specifically its binding to S. aureus surface.
- To assess the in vivo therapeutic potential of Def and Van combination therapy in a murine model of S. aureus bacteremia.
Main Methods:
- In vitro time-kill assays were performed using MRSA and VISA strains exposed to Def, Van, or both.
- Flow cytometry was utilized to quantify the impact of Def on Van's surface binding to S. aureus.
- A murine bacteremia model was employed to compare the in vivo efficacy of Def, Van, and their combination in reducing bacterial burden and infection severity.
Main Results:
- Combination therapy with Def and Van significantly reduced MRSA and VISA viability in vitro compared to monotherapy or controls (p < 0.005).
- Deferasirox treatment was correlated with enhanced surface binding of vancomycin to S. aureus cells.
- In vivo, Def + Van significantly decreased bacterial load in mouse kidneys and spleen and reduced overall infection severity for both MRSA and VISA strains.
Conclusions:
- Deferasirox enhances the killing efficacy of vancomycin against MRSA and VISA, both in vitro and in vivo.
- The enhanced killing appears to be mediated, at least in part, by increased vancomycin binding to the staphylococcal surface.
- Iron chelation represents a promising adjunctive therapeutic approach for treating challenging S. aureus infections, including resistant strains.
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