Diabetes drug improves antibacterial treatments

image: Metformin-capped Cu2(OH)3Cl nanosheets are fabricated for antibacterial and wound healing chemodynamic applications.
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Credit: Nano Research

Old dogs may not learn new tricks, but old drugs can, according to a China-based research team. The collaboration revealed that metformin, a small-molecule drug that has been used to treat type II diabetes for more than 50 years, can improve the efficacy and effectiveness of antibacterial treatments for rapid wound healing in mice.

They published their results on May 19 in Nano-research. (DOI 10.1007/s12274-022-4457-5)

“Overuse of antibiotics has led to severe bacterial resistance, with an estimated 1.27 million deaths in 2019 from multidrug-resistant bacterial infections,” said co-corresponding author Linlin Li, a professor at the Institute of Beijing Nanoenergy and Nanosystems, Chinese Academy of Sciences. “Bacterial resistance poses a deadly threat to human health. Non-antibiotic antibacterial technologies and antibacterial nanoagents with specific catalytic activities not only produce toxic substrates to directly kill bacteria – including antibiotic-resistant bacteria – but can also reduce the risk of bacteria developing drug resistance.

According to Li, chemodynamic therapy has attracted considerable attention since its development in 2016 as a potential companion to cancer therapies, bacterial inactivation and infectious disease treatments. The therapy uses nanomaterials containing transition metals that react with hydrogen peroxide to produce a hydroxyl radical, which weakens and kills diseased or infected cells, making them more susceptible to direct treatment.

“The reaction generates a toxic hydroxyl radical, which destroys the cell surface structure and causes its internal components to leak out,” Li said. inflamed, so the therapy is highly specific in reducing off-target toxicity. Bacterial infections also tend to be accompanied by microenvironmental alterations favorable to chemodynamic therapy.

The researchers set out to improve the antibacterial potency of a nanoagent, while reducing toxicity to healthy cells – a risk that can be difficult to control due to the invasive nature of the infection.

“Positively charged portions of molecules, such as quaternary ammonium salts and chitosan, have intrinsic antibacterial effects by adsorbing to the cell wall of bacteria, producing a compartment resistance effect, and ultimately inducing bacterial death,” Li said. “Metformin is a positively charged small molecule drug with reported anticancer, immunomodulatory, and antibacterial effects. We hypothesized that integrating metformin with a chemodynamic therapy nanoagent would enhance the antibacterial effect.

The researchers mixed the metformin with copper chloride to form nanosheets whose surface was capped with the metformin molecules, enhancing the positive charge of the nanoagent and enhancing the antibacterial effects, according to Li.

In vitro tests revealed a biocompatible nanoplatform with better dispersity than a nanoagent without metformin, and higher antibacterial activity.

“Compared to previous reports that used metformin as an antibacterial agent alone, excellent antimicrobial effects were obtained in our experiments using lower concentrations of nanosheets with a very short action time,” said Li, who has noted that they were also studying the effects of metformin in other biomedical applications to develop more therapies.

To further test the metformin-capped nanosheets, the researchers established a model of staph infection in the skin of mice. The mice were divided into five groups, each of which received a treatment variant. The group that received both the metformin nanosheets and supplemental hydrogen peroxide to promote hydroxyl radical production had the fastest healing rate, with complete closure by day 12 of treatment.

“This work not only develops an effective chemodynamic therapy nanoagent as an alternative antibacterial agent to treat skin wound infections, but also provides insights into finding new uses for old drugs,” Li said.

Li is also affiliated with the Center on Nanoenergy Research, School of Physical Science and Technology, Guangxi University, and the School of Nanoscience and Technology, University of CAS. Other contributors include Xueyu Wang, Teng Xu and co-corresponding author Shu Yan, 306th Clinical College of PLA, The Fifth Clinical College, Anhui Medical University; Shaobo Wang, Shuncheng Yao, Yunchao Zhao, Zeyu Zhang and Tian Huang, Beijing Institute of Nanoenergy and Nanosystems, CAS; Xueyu Wang and Jiao Gao, Characteristic Medical Center of the PLA Strategic Support Force. Xueyu Wang and Xu are also affiliated with the Beijing Institute of Nanoenergy and Nanosystems, CAS, and the PLA Strategic Support Force Characteristic Medical Center. Shaobo Wang, Zhao, Zhang and Huang are also affiliated with the Center on Nanoenergy Research, School of Physical Science and Technology, Guangxi University. Yao is also affiliated with CAS University’s School of Nanoscience and Technology.

The National Natural Science Foundation of China and the National Young Talent Support Program have supported this work.

The document is also available on SciOpen (https://www.sciopen.com/article/10.1007/s12274-022-4457-5) by Tsinghua University Press.

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