Scientists have discovered that metformin, a longtime diabetes drug, can help fight against antibiotic-resistant bacteria as part of a non-antibiotic antibacterial technology.
A research team in China has repurposed metformin, a small molecule drug that has been used to treat type II diabetes for more than 50 years – as an additional support for antibacterial treatments. Metformin, they found, can improve the efficiency and efficacy of antibacterial treatments for quick wound-healing in mice.
Their findings were published in the journal Nano Research this month.
“The abuse of antibiotics has led to serious bacterial resistance, with about 1.27 million deaths in 2019 due to multidrug-resistant bacterial infections,” says co-corresponding author Linlin Li, professor at Beijing Institute of Nanoenergy and Nanosystems, Chinese Academy of Sciences.
“Bacterial resistance poses a fatal threat to human health. Non-antibiotic antibacterial technologies and antibacterial nano agents with specific catalytic activities not only produce toxic substrates to directly kill bacteria — including antibiotic-resistant bacteria — but can also reduce the risk of the bacteria developing resistance to drugs,” she adds.
Li explains that chemodynamic therapy “has attracted significant attention since it was developed in 2016 as a potential companion for cancer therapies, bacterial inactivation and infectious disease treatments,” a news release notes.
In their study, the authors write that “[r]ecently, the development of chemodynamic therapy (CDT) offers a potential approach for fighting bacteria and treating infectious diseases, in which those CDT nano agents can catalyze the generation of hydroxyl radicals (•OH) to destroy bacteria.”
Chemodynamic therapy uses nanomaterials containing transition metals that react with hydrogen peroxide to produce hydroxyl radical. Hydroxyl radical acts on infected or diseased cells, weakening and killing them, making it possible to directly treat them.
“The reaction generates toxic hydroxyl radical, which destroys the cell surface structure and causes the cell to leak its internal components,” says Li.
“The nano agents only catalyze hydroxyl radical generation at the site of tumor or inflamed tissues, so the therapy is highly specific to reduce off-target toxicity. Bacterial infections also tend to be accompanied by microenvironmental alterations that are favorable for chemodynamic therapy.”
The scientists worked on a twofold solution: One, they had to improve the antibacterial power of a nano agent, and two, they had to lower the toxicity to healthy cells. This risk could be hard to keep in check, because of the invasive nature of infection.
“Positively charged molecule parts, such as quaternary ammonium salts and chitosan, have intrinsic antibacterial effects through adsorbing on the bacteria cell wall, producing compartment resistance effect and, finally, inducing bacterial death,” says Li.
“Metformin is a positively charged small molecule drug with reported anticancer, immunomodulatory and antibacterial effects. We speculated that the integration of metformin with a chemodynamic therapy nano agent would improve the antibacterial effect.”
The researchers combined metformin with copper chloride and created nanosheets whose surface was capped by the metformin molecules – which, according to Li, enhanced the nano agent’s positive charge and strengthening the antibacterial effects.
When they conducted in vitro tests, they found that the biocompatible nanoplatform has a better dispersity – a measure of the heterogeneity of sizes of molecules or particles in a mixture – than a nano agent without metformin, and higher antibacterial activity.
“Compared to previous reports that used metformin as an antibacterial agent alone, excellent antimicrobial effects were achieved in our experiments using lower concentrations of the nanosheets with very short action time,” Li says.
According to the news release, she also “noted that they are also studying the effects of metformin in other biomedical applications to develop more therapies.”
The researchers wanted to test the metformin-capped nanosheets so they used mice to simulate a staph infection on their skin. The subjects were divided into five groups, receiving a variation of a treatment.
The group of mice that received both the metformin nanosheets and additional hydrogen peroxide to enhance the production of hydroxyl radical ended up with the fastest wound healing rate – their wound had completely closed by day 12 of treatment.
The researchers write “In vivo [tested on mice] results demonstrated that [Cu2(OH)3Cl nanosheets] accelerated the tissue regeneration of staphylococcus aureus-infected dermal wounds.”
“This work not only develops an efficient chemodynamic therapy nano agent as an alternative antibacterial agent to treat skin wound infections, but it also provides ideas about discovering new uses for old drugs,” Li says.