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An ultrasound activable metal-phenolic network nano-antibiotics for in vivo on-site infection therapy

超声激活的金属多酚配位纳米抗生素在体内抗耐药 菌治疗中的应用

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Abstract

Antibiotic is one of the greatest discoveries in human history. It has drastically promoted modern medicine and extended the average human lifespan. However, antibiotic resistance has become a global crisis today and the development of novel antibiotics is highly demanded. The traditional antibiotics not only kill the pathogen but also damage the resident microbiome in the human body, thus promoting antibiotic resistance and elevating the risk of patients for new infection. Here, we fabricated an activable metal-phenolic network nano-antibiotics (PEG-P18-Ag NPs) that can be selectively activated on the site of infection, thus presumably avoiding their impacts on the resident microbiome. We showed that PEG-P18-Ag NPs per se do not have any antibacterial activity. However, upon activation by the ultrasound, they triggered the generation of reactive oxygen species. Consequently, PEG-P18-Ag NPs remarkably killed various multi-drug resistant bacteria and established biofilms in vitro and in vivo. By RNA sequencing, we revealed that activated PEG-P18-Ag NPs produced a profound damaging effect on the bacteria. Collectively, we provided a novel approach for the new generation of antibiotics that selectively target infected bacteria.

摘要

抗生素的滥用引发了漫延全球的抗生素耐药危机. 多重耐药细 菌的出现对人类生命健康构成了极大的威胁. 此外, 传统抗生素在体内 杀死病原菌的同时, 对人体正常微生物菌群的破坏也增加了导致其他 感染和疾病的风险. 因此, 新型抗生素的研发显得日益紧迫. 在本文中, 我们合成了一种超声激活的金属多酚配位纳米抗生素(PEG-P18-Ag NPs), 其可在感染部位被选择性激活, 从而避免了对体内正常微生 物群体的影响. 实验证实PEG-P18-Ag NPs在未激活时不具有抗菌活性. 经超声激活后, 其可引起大量活性氧物种(ROS)的产生, 从而杀死多种 多重耐药菌及生物膜. 通过RNA测序技术, 本文进一步证实PEG-P18-Ag NPs对细菌细胞的细胞膜、核糖体、染色质及鞭毛等结构造成了严 重损伤. 总之, 本研究合成了一种靶向体内耐药菌的新型抗生素, 可实 现广谱、快速和可控的抗多重耐药菌治疗.

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Acknowledgements

This study was supported by the National Natural Science Foundation of China (32171318 and 32101069), University of Macau (MYRG2019-000050-FHS and MYRG2020-00046-FHS), the Science and Technology Development Fund, Macau SAR (0109/2018/A3, 0058/2018/A2, 0113/2019/A2, 0103/2021/A and 0002/2021/AKP), and Shenzhen Science and Technology Innovation Commission, Shenzhen-Hong Kong-Macau Science and Technology Plan C (SGDX20201103093600004). We are thankful to the kind assistance and support from the Animal Research Core and Biological Imaging and Stem Cell Core, Faculty of Health Sciences, University of Macau.

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  1. These authors contributed equally to this work.

Authors and Affiliations

  1. Cancer Center and Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Macau SAR, 999078, China

    Chang Lu  (卢畅), Ye Tian  (田野), Hao Tian  (田浩), Bei Li  (李蓓), Jun Zheng  (郑军) & Yunlu Dai  (代云路)

  2. MoE Frontiers Science Center for Precision Oncology, University of Macau, Macau SAR, 999078, China

    Bei Li  (李蓓) & Yunlu Dai  (代云路)

  3. School of Life Sciences, Sun Yat-Sen University, Guangzhou, 510006, China

    Bo Peng  (彭博)

  4. Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao, 266071, China

    Bo Peng  (彭博)

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  1. Chang Lu  (卢畅)
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Contributions

Lu C and Tian Y designed and carried out the experiments. Lu C took the lead in performing the experiments, analyzing the data and writing the manuscript with input from all authors. Tian Y synthesized the nanoparticles and evaluated the characterizations of nanoparticles. Tian H assisted in the nanoparticle synthesis. Li B helped with funding acquisition. Peng B provided several bacteria strains. Zheng J conceived the presented idea and assisted in the funding and supervising of the project. Dai Y conceived the study and was in charge of overall direction and planning. All authors discussed the results and commented on the manuscript.

Corresponding authors

Correspondence to Jun Zheng  (郑军) or Yunlu Dai  (代云路).

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Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary information

Supporting data are available in the online version of the paper.

Chang Lu received her Master’s degree from the School of Laboratory Medicine, Chongqing Medical University, China. Now she is pursuing her PhD degree at the Faculty of Health and Sciences, University of Macau. Her research mainly focuses on the development of novel antibacterial compounds and materials for controlling bacterial antibiotic persistence and resistance.

Ye Tian received her BD degree (2017) and MD degree (2020) from the School of Public Health, Xiamen University in China. From August 2020 to now, she is a PhD student at the Faculty of Health Sciences, University of Macau. Her research mainly focuses on the synthesis and application of nanomedicines.

Jun Zheng is an associate professor at the Faculty of Health Sciences, University of Macau. He received his PhD degree from the Department of Biological Sciences, National University of Singapore. Then he joined Prof. John Mekalanos’ laboratory at the Department of Microbiology and Molecular Genetics, Harvard Medical School as a postdoctoral fellow. His research focuses on the mechanism of bacterial death, bacterial pathogenesis, and the development of new antibacterial agents.

Yunlu Dai is an assistant professor at the Faculty of Health Sciences, University of Macau. He received his PhD degree in 2014 from Changchun Institute of Applied Chemistry, Chinese Academy of Sciences. He then moved to the University of Melbourne as a research fellow. In 2016, he worked as a postdoctoral fellow at the National Institutes of Health. He initiated his independent research program in 2018 at the University of Macau. His research focuses on the multifunctional hybrid nanomaterials for biomedical application.

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Lu, C., Tian, Y., Tian, H. et al. An ultrasound activable metal-phenolic network nano-antibiotics for in vivo on-site infection therapy. Sci. China Mater. 66, 395–406 (2023). https://doi.org/10.1007/s40843-022-2125-1

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  • DOI: https://doi.org/10.1007/s40843-022-2125-1

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