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Inhibition of the ATP synthase increases sensitivity of Escherichia coli carrying mcr-1 to polymyxin B

The Journal of Antibiotics volume 77, pages 685–696 (2024)Cite this article

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Abstract

Bacterial infections caused by multidrug-resistant (MDR) gram-negative strains carrying the mobile colistin resistance gene mcr-1 are serious threats to world public health due to the lack of effective treatments. Inhibition of the ATP synthase makes bacteria such as Staphylococcus aureus and Klebsiella pneumoniae more sensitive to polymyxin. This provides new strategies for treating infections caused by polymyxins-resistant bacteria carrying mcr-1. Six mcr-1-positive strains were isolated from clinical samples, and all were identified as Escherichia coli. Here we investigated several ATP synthase inhibitors, N,N’-dicyclohexylcarbodiimide (DCCD), resveratrol, and piceatannol, for their antibacterial effects against the mcr-1-positive strains combined with polymyxin B (POL). Checkerboard assay, time-kill assay, biofilm inhibition and eradication assay indicated the significant synergistic effect of ATP synthase inhibitors/POL combination in vitro. Meanwhile, mouse infection model experiment was also performed, showing a 5 log10 reduction of the pathogen after treatment with the resveratrol/POL combination. Moreover, adding adenosine disodium triphosphate (Na2ATP) could inhibit the antibacterial effect of the ATP synthase inhibitors/POL combination. In conclusion, our study confirmed that inhibition of ATP production could increase the susceptibility of bacteria carrying mcr-1 to polymyxins. This provides a new strategy against polymyxins-resistant bacteria infection.

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Data availability

The datasets used and analyzed during the current study are available from the corresponding author upon reasonable request. Most of the data is included in this published article.

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Funding

This work was supported by grants from the National Natural Science Foundation of China (32200159, 82272352, 82130065).

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Author notes

  1. These authors contributed equally: Zheng Fan, Zhoufei Li, Tongtong Fu

Authors and Affiliations

  1. Department of Bacteriology, Capital Institute of Pediatrics, Beijing, 100020, China

    Zheng Fan, Zhoufei Li, Tongtong Fu, Yanling Feng, Yuchen Chen, Hongbo Liu, Xiaohu Cui, Hanqing Zhao, Guanhua Xue, Jinghua Cui, Chao Yan, Lin Gan, Junxia Feng, Ziying Xu, Zihui Yu & Jing Yuan

  2. Graduate School of Peking Union Medical College, Beijing, China

    Zhoufei Li

  3. University of Edinburgh, Edinburgh, UK

    Bing Du

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Contributions

JY, ZF, and ZL designed the experiments. ZF, ZL, TF, YF, BD, XC, RZ, and HZ performed the experiments. The other authors analyzed the results. ZF and ZL wrote the manuscript. JY and ZF revised the manuscript. All authors reviewed the manuscript.

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Correspondence to Jing Yuan.

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The authors declare no competing interests.

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We declared that all animal experiments complied with the US and Chinese national guidelines for the use of animals in research. The protocol was approved by the Capital Institute of Pediatrics (permission number DWLL2023011).

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Fan, Z., Li, Z., Fu, T. et al. Inhibition of the ATP synthase increases sensitivity of Escherichia coli carrying mcr-1 to polymyxin B. J Antibiot 77, 685–696 (2024). https://doi.org/10.1038/s41429-024-00753-z

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