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 in vitro and in vivo activity of d-serine alone and in combination with β -lactams against methicillin-resistant Staphylococcus aureus (MRSA) strains, and to explore the possible sensitization mechanisms. The activity of d-serine, β -lactams alone and in combinations was evaluated both in vitro by standard MICs, time–kill curves and checkerboard assays, and in vivo by murine systemic infection model as well as neutropenic thigh infection model. An in vitro synergistic effect was demonstrated with the combination of d-serine and β -lactams against MRSA standard and clinical strains. Importantly, the combinations enhanced the therapeutic efficacy in the animal models as compared to β -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 β -lactams against MRSA strains both in vitro and in vivo . Considering the relatively good safety of d-serine alone or in combination with β -lactams, d-serine is worth following up as new anti-MRSA infection strategies.

Hypericin enhances β-lactam antibiotics activity by inhibiting sarA expression in methicillin-resistant Staphylococcus aureus

“…It is known that mecA, encoding penicillin binding protein 2a (PBP2a), mediates the resistance to β -lactam antibiotics in MRSA 35 . In addition, we have recently demonstrated the important role of the global regulator, sarA , in β -lactam antibiotics resistance in MRSA 10 .…”

“…To further define the effect of HYP on OXA susceptibility against MRSA in vivo , a well-characterized murine bacteremia model was used 34 . All the animal studies complied with the ARRIVE guidelines 35 and the Institutional Animal Care and Use Committee of Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center (Los Angeles, CA, USA) approved the animal study protocol. CD1 male mice (∼6 weeks) were infected by using exponential phase of MRSA JE2 cells via tail vein (10 8 CFU/mouse).…”

Benefits and applications of microwave-assisted synthesis of nitrogen containing heterocycles in medicinal chemistry

“…97 Recently, a combination of D-serine with b-lactam antibiotics was tested for activity against Staphylococcus aureus and showed promising results. 98…”

Ultra-short-course and intermittent TB47-containing oral regimens produce stable cure against Buruli ulcer in a murine model and prevent the emergence of resistance for Mycobacterium ulcerans

“…Meanwhile, TB47 at 25 mg/kg with expanding treatment duration, the time-to-relapse was prolonged and 80% mice treated for 2 weeks showed no relapse at least 23 weeks after treatment completion. A combination of new compounds and available antibiotics may enhance the therapeutic efficacy, such as d -serine and hypericin had synergistic activity in combination with β -lactams against methicillin-resistant Staphylococcus aureus in vivo 10 , 11 . So we speculated increasing TB47 dose and combining TB47 with 1 or 2 other drugs currently available could possibly cure BU quickly.…”