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Theranostics 2021; 11(17):8152-8171. doi:10.7150/thno.55334 This issue Cite

Research Paper

Fructose-coated Ångstrom silver prevents sepsis by killing bacteria and attenuating bacterial toxin-induced injuries

Hao Yin^1,2,3, Mao Zhou⁴, Xia Chen⁴, Teng-Fei Wan¹, Ling Jin¹, Shan-Shan Rao^1,5, Yi-Juan Tan^1,2,3, Ran Duan⁶, Yu Zhang⁷, Zhen-Xing Wang^1,2,3, Yi-Yi Wang^1,2,3, Ze-Hui He¹, Ming-Jie Luo^1,2,3,5, Xiong-Ke Hu¹, Yang Wang^2,3,8, Wei-Yi Situ^2,3, Si-Yuan Tang⁵, Wen-En Liu⁴, Chun-Yuan Chen^1,2,3✉, Hui Xie^{1,2,3,6,9,10,11✉}

1. Department of Orthopedics, Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
2. Angmedicine Research Center of Central South University, Changsha, Hunan 410008, China
3. Xiangya Hospital of Central South University - Amcan Pharmaceutical Biotechnology Co. Ltd. Joint Research Center, Changsha, Hunan 410008, China
4. Department of Clinical Laboratory, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
5. Xiangya School of Nursing, Central South University, Changsha, Hunan 410013, China
6. Department of Sports Medicine, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
7. Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan, China
8. Institute of Integrative Medicine, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
9. Hunan Key Laboratory of Organ Injury, Aging and Regenerative Medicine, Changsha, Hunan 410008, China
10. Hunan Key Laboratory of Bone Joint Degeneration and Injury, Changsha, Hunan 410008, China
11. National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China

✉ Corresponding authors: Hui Xie (huixieedu.cn); Chun-Yuan Chen (chency19edu.cn).

Abstract

Serious infection caused by multi-drug-resistant bacteria is a major threat to human health. Bacteria can invade the host tissue and produce various toxins to damage or kill host cells, which may induce life-threatening sepsis. Here, we aimed to explore whether fructose-coated Ångstrom-scale silver particles (F-AgÅPs), which were prepared by our self-developed evaporation-condensation system and optimized coating approach, could kill bacteria and sequester bacterial toxins to attenuate fatal bacterial infections.

Methods: A series of in vitro assays were conducted to test the anti-bacterial efficacy of F-AgÅPs, and to investigate whether F-AgÅPs could protect against multi-drug resistant Staphylococcus aureus (S. aureus)- and Escherichia coli (E. coli)-induced cell death, and suppress their toxins (S. aureus hemolysin and E. coli lipopolysaccharide)-induced cell injury or inflammation. The mouse models of cecal ligation and puncture (CLP)- or E. coli bloodstream infection-induced lethal sepsis were established to assess whether the intravenous administration of F-AgÅPs could decrease bacterial burden, inhibit inflammation, and improve the survival rates of mice. The levels of silver in urine and feces of mice were examined to evaluate the excretion of F-AgÅPs.

Results: F-AgÅPs efficiently killed various bacteria that can cause lethal infections and also competed with host cells to bind with S. aureus α-hemolysin, thus blocking its cytotoxic activity. F-AgÅPs inhibited E. coli lipopolysaccharide-induced endothelial injury and macrophage inflammation, but not by directly binding to lipopolysaccharide. F-AgÅPs potently reduced bacterial burden, reversed dysregulated inflammation, and enhanced survival in mice with CLP- or E. coli bloodstream infection-induced sepsis, either alone or combined with antibiotic therapy. After three times injections within 48 h, 79.18% of F-AgÅPs were excreted via feces at the end of the 14-day observation period.

Conclusion: This study suggests the prospect of F-AgÅPs as a promising intravenous agent for treating severe bacterial infections.

Keywords: Ångstrom-scale silver particles, bacterial infection, α-hemolysin, lipopolysaccharide, inflammation

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