Development of a dual oral antibiotics therapy against MRSA Infections

Abstract

Abstract Methicillin resistant Staphylococcus aureus (MRSA) is a major global concern causing significant morbidity and mortality worldwide. Current MRSA treatment such as vancomycin, or the other available antibiotics are limited due to its dwindling efficacy, potential serious side effects, high costs and more importantly resistance were repeatedly reported to these medications. Thus, new strategies are in urgent need to treat MRSA. Antibiotics combination therapy is a promising strategy to overcome the problem. Previous high throughput screening of several FDA approved drug library by our group identified an oral antibiotic, X augmenting Y against MRSA strain USA300. This study aims to characterize and evaluate this dual oral antibiotic against different MRSA clinical strains. To investigate the invitro synergy of the combination, checkerboard assay and minimum biofilm inhibitory concentration assay was performed. Galleria Mellonella model was used to assess the in-vivo synergistic activity of the combinations. Checkboard assay revealed highly synergetic effect of this combination against clinical MRSA strains. Where the MIC of Y reduced by about 256-fold in some strains such as USA500 strain. Y-X combination also showed greater antibiofilm activity (P, < 0.0001) comparing to monotherapy against Staphylococcus aureus biofilms. In a waxworm Galleria Mellonella infection model X and Y combination was able to clear MRSA infection almost similarly to Vancomycin monotherapy. In conclusions, the combinations of Y plus X showed significant synergism in both invitro and in vivo study using waxworm Galleria Mellonella infection model. Thus, this combination could be a promising strategy for treatment of MRSA infection.