Cajanin stilbene acid: A direct inhibitor of colistin resistance protein MCR-1 that restores the efficacy of polymyxin B against resistant Gram-negative bacteria

文献类型： 外文期刊

第一作者： Jia, Yue

作者： Jia, Yue;Zhang, Wanjiang;Liu, Siguo;Liu, Juzhao;Hua, Xin;Hua, Xin;Efferth, Thomas;Yang, Qin;Yang, Qin;Hua, Xin;Liu, Siguo;Efferth, Thomas

作者机构：

关键词： Cajanin stilbene acid; Direct inhibitor; Gram-negative bacteria; MCR-1; Sensitivity recovery

期刊名称：PHYTOMEDICINE （ 影响因子：7.9； 五年影响因子：6.8 ）

ISSN： 0944-7113

年卷期： 2023 年 114 卷

页码：

收录情况： SCI

摘要： Background: The resistance of Gram-negative bacteria to polymyxin B, caused by the plasmid-mediated colistin resistance gene mcr-1, which encodes a phosphoethanolamine transferase (MCR-1), is a serious threat to global public health. Therefore, it is urgent to find new drugs that can effectively alleviate polymyxin B resistance. Through the screening of 78 natural compounds, we found that cajanin stilbene acid (CSA) can significantly restore the susceptibility of polymyxin B to mcr-1 positive Escherichia coli (E. coli).Purpose: In this study, we tried to evaluate the ability of CSA to restore the susceptibility of polymyxin B towards the E. coli, and explore the mechanism of sensitivity recovery.Study design and methods: Checkerboard MICs, time-killing curves, scanning electron microscope, lethal and semi-lethal models of infection in mice were used to assess the ability of CSA to restore the susceptibility of polymyxyn to E. coli. The interaction between CSA and MCR-1 was evaluated using surface plasmon resonance (SPR), and molecular docking experiments.Results: Here, we find that CSA, a potential direct inhibitor of MCR-1, effectively restores the sensitivity of E. coli to polymyxin B. CSA can restore the sensitivity of polymyxin B to drug-resistant E. coli, and the MIC value can be reduced to 1 mu g/ml. The time killing curve and scanning electron microscopy results also showed that CSA can effectively restore polymyxin B sensitivity. In vivo experiments showed that the simultaneous use of CSA and polymyxin B can effectively reduce the infection of drug-resistant E. coli in mice. SPR and molecular docking experiments confirmed that CSA strongly bound to MCR-1. The 17-carbonyl oxygen and 12-and 18-hydroxyl oxygens of CSA were the key sites binding to MCR-1.Conclusion: CSA is able to significantly restore the sensitivity of polymyxin B to E. coli in vivo and in vitro. CSA inhibits the enzymatic activity of the MCR-1 protein by binding to key amino acids at the active center of the MCR-1 protein.

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