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Synergistic Antibacterial Activity of Meropenem and Imipenem in Combination with Diazabicyclooctane Derivatives

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Abstract

The diazabicyclooctane (DBO) has emerged as the attractive motif for the development of new β-lactamase inhibitors after the clinical approval of avibactam and relebactam. We are striving at improving the lactamase inhibition strength and antibacterial spectrum of the DBO derivatives. We synthesized the substituted-amidine derivatives (5a–5j) of the DBO, and determined the antibacterial efficacy of the two β-lactam drugs i.e. imipenem and meropenem, in combination with compounds 5a–5j. All these derivatives lowered the MIC values of the imipenem and meropenem, indicating their β-lactamase inhibition profile, however in variable strength. The best results were obtained when the compounds 5a–5j were combined with meropenem indicating the better association of these compounds with meropenem in comparison to imipenem. With meropenem, compounds 5a and 5b proved to be the most potent exhibiting the highest antibacterial efficacy against five out of ten microbial strains. Moreover, the MIC data showed that β-lactamase inhibition strength of compounds 5a and 5b was comparable to relebactam in eight out of ten bacterial strains.

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Funding

Ministry of Science and Technology, P.R. China is gratefully Acknowledged for the award of foreign expert program to Dr. Haikang Yang and Dr. Zafar Iqbal. This work was supported by the grant from Science and Technology Department of Ningxia, P.R. China (no. 2018BCG01001).

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Authors and Affiliations

  1. Ningxia Academy of Agriculture and Forestry Sciences, No. 590, Huanghe East Road, **feng District, Yinchuan, 750002, Ningxia, China

    Jian Sun, Lili He, **gwen Ji, Lijuan Zhai, **bo Ji, Dong Tang, Yangxiu Mu, Yuanyu Gao, Lin Wang, Haikang Yang, Zafar Iqbal & Zhixiang Yang

  2. College of Pharmacy, Ningxia Medical University, Shengli Street, **ngqing District, Yinchuan, 750004, Ningxia, China

    Xueqin Ma

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  1. Jian Sun
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  2. Lili He
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  3. **gwen Ji
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  4. Lijuan Zhai
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  10. Lin Wang
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Correspondence to Zafar Iqbal or Zhixiang Yang.

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Sun, J., He, L., Ji, J. et al. Synergistic Antibacterial Activity of Meropenem and Imipenem in Combination with Diazabicyclooctane Derivatives. Russ J Gen Chem 92, 2070–2081 (2022). https://doi.org/10.1134/S1070363222100218

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