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Methimazole and α-lipoic acid as metallo-β-lactamases inhibitors

The Journal of Antibiotics volume 75, pages 282–286 (2022)Cite this article

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Abstract

The emergence of bacterial resistance poses a serious threat to public health. One of the most important resistance mechanisms against β-lactam antibiotics is the production of metallo-β-lactamases (MBLs). In this study, α-lipoic acid (LA) and methimazole (MMI), which have been used in clinical practice as non-antibacterial drugs and as a supplement, were chosen to explore their potential to be metallo-β-lactamases inhibitors (MBLIs). Enzyme inhibition assays showed that LA and MMI had moderate inhibitory activity against NDM-1 but no activity against VIM-2 and IMP-7. Antibacterial assays to determine synergy, demonstrated that the combination of LA or MMI with meropenem (MER) reduced the MIC value of MER against NDM-1 producing E. coli 16 times and 4 times, respectively, lower than that of MER alone. The fractional inhibitory concentration index (FICI) values were calculated to be less than 0.5, indicating that both LA and MMI had synergistic antibacterial effects with MER against all three MBLs expressing E. coli strains. The time-kill studies also suggested that LA and MMI were effective in restoring the antibacterial effect of MER. These findings revealed that LA and MMI are potential carbapenem enhancers, and provide a starting point for the development of potent MBLIs.

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Acknowledgements

This work was funded by Pearl River Nova Program of Guangzhou (201710010013) and Youth Program of Military Medical Science and Technology (19QNP041).

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Authors and Affiliations

  1. Department of Pharmacy, General Hospital of Southern Theatre Command of PLA, Guangzhou, 510010, China

    Bing Zhang, Yan Yang, Taoyang Huang & Zhihui Jiang

  2. School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China

    Bing Zhang, Yan Yang, Jin Yuan, Lei Shi & Zhihui Jiang

  3. Department of Clinical Pharmacy, General Hospital of Southern Theatre Command of PLA, Guangzhou, 510010, China

    Jin Yuan & Lei Shi

  4. Department of Laboratory Medicine, General Hospital of Southern Theatre Command of PLA, Guangzhou, 510010, China

    Lidan Chen

  5. Department of Emergency Medicine, General Hospital of Southern Theatre Command of PLA, Guangzhou, 510010, China

    Huasheng Tong

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  1. Bing Zhang
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Contributions

ZJ and LS designed research and analyzed data. BZ, YY, JY, LC, TH, and HT conducted experiments. ZJ and LS supervised the whole study, wrote and revised the manuscript. All authors approved the final version of the manuscript.

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Correspondence to Lei Shi or Zhihui Jiang.

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Zhang, B., Yang, Y., Yuan, J. et al. Methimazole and α-lipoic acid as metallo-β-lactamases inhibitors. J Antibiot 75, 282–286 (2022). https://doi.org/10.1038/s41429-022-00513-x

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