In vitro and in vivo activity of d-serine in combination with β-lactam antibiotics against methicillin-resistant Staphylococcus aureus

Abstract

As d-amino acids play important roles in the physiological metabolism of bacteria, combination of d-amino acids with antibiotics may provide synergistic antibacterial activity. The aim of the study was to evaluate <i>in vitro</i> and <i>in vivo</i> activity of d-serine alone and in combination with <i>β</i>-lactams against methicillin-resistant <i>Staphylococcus aureus</i> (MRSA) strains, and to explore the possible sensitization mechanisms. The activity of d-serine, <i>β</i>-lactams alone and in combinations was evaluated both <i>in vitro</i> by standard MICs, time-kill curves and checkerboard assays, and <i>in vivo</i> by murine systemic infection model as well as neutropenic thigh infection model. An <i>in vitro</i> synergistic effect was demonstrated with the combination of d-serine and <i>β</i>-lactams against MRSA standard and clinical strains. Importantly, the combinations enhanced the therapeutic efficacy in the animal models as compared to <i>β</i>-lactam alone groups. Initial mechanism study suggested possible revision of d-alanine-d-alanine residue to d-alanine-d-serine in peptidoglycan by adding of d-alanine in the medium, which may cause decreased affinity to PBPs during transpeptidation. In conclusion, d-serine had synergistic activity in combination with <i>β</i>-lactams against MRSA strains both <i>in vitro</i> and <i>in vivo</i>. Considering the relatively good safety of d-serine alone or in combination with <i>β</i>-lactams, d-serine is worth following up as new anti-MRSA infection strategies.