Iron acquisition is a
virulence factor for Staphylococcus aureus. We assessed the efficacy of the
iron chelator,
deferasirox (
Def), alone or in combination with
vancomycin (Van) against two methicillin-resistant S. aureus (MRSA) strains in vitro and in a murine
bacteremia model. In vitro time-kill assays were carried out against MRSA or
vancomycin-intermediate S. aureus (VISA) strains. The impact of
Def on Van binding to the surface of S. aureus was measured by flow cytometry. Furthermore, we compared the efficacy of
Def, Van, or both drugs in treating S. aureus
bacteremia in a murine model. Combination
therapy reduced MRSA and VISA viability in vitro versus either
drug alone or untreated controls (p < 0.005); this outcome was correlated with enhanced Van surface binding to S. aureus cells. In vivo,
Def + Van combination
therapy significantly reduced the bacterial burden in mice kidneys (p = 0.005) and spleen (p < 0.001), and reduced the severity of
infection with MRSA or VISA strains compared to placebo-treated mice. Our results show that
Def enhances the in vitro and in vivo capacity of Van-mediated MRSA killing via a mechanism that appears to involve increased binding of Van to the staphylococcal surface.
Iron chelation is a promising, novel adjunctive therapeutic strategy for MRSA and VISA
infections.