Original articles
Qing Wang, Yuemeng Lv, Jing Pang, Xue Li, Xi Lu, Xiukun Wang, Xinxin Hu, Tongying Nie, Xinyi Yang, Yan Q. Xiong, Jiandong Jiang, Congran Li, Xuefu You. In vitro and in vivo activity of D-serine in combination with β-lactam antibiotics against methicillin-resistant Staphylococcus aureus[J]. Acta Pharmaceutica Sinica B, 2019, 9(3): 496-504

In vitro and in vivo activity of D-serine in combination with β-lactam antibiotics against methicillin-resistant Staphylococcus aureus
Qing Wanga, Yuemeng Lva, Jing Panga, Xue Lia, Xi Lua, Xiukun Wanga, Xinxin Hua, Tongying Niea, Xinyi Yanga, Yan Q. Xiongb,c, Jiandong Jianga,d, Congran Lia, Xuefu Youa
a Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China;
b Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, Torrance, CA 90502, USA;
c David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA;
d State Key Laboratory of Bioactive Substances and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
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.
Key words:    MRSA    D-Serine    β-Lactams    Combination    Synergistic effect   
Received: 2018-11-24     Revised:
DOI: 10.1016/j.apsb.2019.01.017
Funds: This study was supported by the National Natural Science Foundation of China (grant numbers 81621064 and 81361138020), CAMS Initiative for Innovative Medicine (Grant No. 2016-I2M-3-014, China), PUMC Youth Fund (grant number 3332013145, China) and National Mega-project for Innovative Drugs (Grant No. 2018ZX09721001, China).
Corresponding author: Congran Li, Xuefu You     Email:cong5885@aliyun.com;xuefuyou@imb.pumc.edu.cn
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Authors
Qing Wang
Yuemeng Lv
Jing Pang
Xue Li
Xi Lu
Xiukun Wang
Xinxin Hu
Tongying Nie
Xinyi Yang
Yan Q. Xiong
Jiandong Jiang
Congran Li
Xuefu You

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