“New Way to Combat Super Bacteria: Nano-Antibiotic Mixed with Metal Ion”

2022-09-12 Research

Professor Kim Dokyoung of the College of Medicine proposed the world’s first nano-antibiotic development strategy that can overcome super bacteria

“Super Bacteria,” also known as “Super Bug,” are resistant to antibiotics and notoriously difficult to treat. In early 2020, in a special report analyzing the progress of new antibiotics in the development pipeline, the World Health Organization (WHO) urged global pharmaceutical companies to ramp up their effort to find new antibiotics to suppress super bacteria. Since developing new antibiotics is less lucrative than other medicine due to the massive R&D cost required, pharmaceutical companies are generally not eager to invest in new antibiotics candidates. However, there still are many dedicated researchers around the world who are working on identifying new antibiotic substance or improving existing drugs.

“Drug-metal ion multiple complex” with sceptrin and gold ion can overcome multidrug-resistant bacterial mechanism
Professor Dokyoung Kim of the College of Medicine proposed a completely new antibiotic development strategy for the first time in the world: a drug-metal ion complex. The strategy is to fuse biologically active natural products that has antibacterial potential with certain types of metal ion to create new nanoparticle antibiotics. Professor Kim created a nano-sized drug-metal ion complex by combining sceptrin and ionized gold and demonstrated the antibiotic qualities of the new substance. The research result was featured on the cover paper of the world-renowned scientific journal Nanoscale Horizons (IF=11.684) under the title, “Sceptrin-Au nano-aggregates (SANA) for overcoming drug-resistant Gram-negative bacteria.”

In the past, combating bacterial drug-resistance was trying either bypassing the drug-resistant genetic pathway or discovering a wholly new type of antibiotics. “Drug Repositioning” is one of those methods, which is experimenting with therapeutically effective drugs proven in treating other types of diseases as antibiotics: trying successful anticancer drugs as antibiotics, for instance. Sceptrin, used by Professor Kim, is an ocean-based natural product with various biological properties including anticancer effect. He said, “Sceptrin has a moderate level of antibacterial quality, but it is not strong enough to breach the bacterial drug resistance on its own. We developed a new delivery strategy to effectively bypass drug resistance by turning a new antibiotic, which is not strong enough on its own against multidrug-resistant bacteria, into a drug-metal ion multiple complex form.”

There are various mechanisms for bacteria to attain resistance to multiple antibiotics. Some strains of bacteria might have intrinsic genetic resistance to certain antibiotics, or some might be able to quickly expel the drug out of their system. The first type can be countered by finding new antibacterial substance, and the second type can be combated by making the drug difficult to be ejected by bacteria. Professor Kim’s research has introduced a new delivery strategy to neutralize the resistance mechanism of multidrug-resistant bacteria, thereby increasing the chance of existing antibiotics to become more effective with the new delivery method. Antibiotics that can fuse with metal ions can be developed as new drug-metal ion multiple complex antibiotics. Professor Kim said, “This strategy, from the bacteria’s point of view, is like the same old weakling they thought they could safely ignore suddenly came back all bulked up with fearsome muscle. While bacteria will eventually become resistant to even this sceptrin-gold ion aggregate antibiotic, we now have a new strategy to keep creating effective antibiotics in this race against multidrug-resistant bacteria with relative ease.”

SANA is not a completely new material but a new spin to maximize the value of existing substances
The new formular of sceptrin and ionized gold that Professor Kim created is named “Sceptrin-Au nano-aggregates (SANA).” As metals need to be bound to organic substances, the selectivity of sceptrin with compatible metal needs to be identified first, and then the biological toxicity of the metal must also be determined. If the metal is harmful to the human body, it cannot be used for drug formulation regardless of its affinity with sceptrin. Amines have good bonding properties with metals, and the level of amines in the substance is directly correlated with its ability to bond with metals. Sceptrin satisfies this condition well. While Professor Kim explored numerous combinations of metal and antibiotic substances, the fusion of gold and sceptrin was determined to be most effective. In addition, gold is low in biological toxicity that it poses little risk to the human body when exposed in the extremely small amount that SANA uses.

Once gold ion and sceptrin were fused, the new substance was studied to determine which of the two component materials was more effective against multidrug-resistant bacteria. Gold ion or sceptrin alone had no efficacy on its own, but the aggregate SANA showed high potency. Professor Kim used SANA on four representative multidrug-resistant bacteria collected from patients who visited the hospital and confirmed the effectiveness. He also identified the minimum dosage of SANA, the minimum concentration that has desirable therapeutic effect, and conducted a toxicity test to ensure patient safety.

Professor Kim said, "Since the chemical structure of sceptrin in SANA remains identical, it can be used clinically in the same way as regular sceptrin, which is much safer than dealing with a wholly new drug with limited prior clinical experience. In the case of gold, it is a familiar material proven to have exceptionally low toxicity, so the risk is minimal in this application. SANA is a new antibiotic in the sense that it is a new spin on existing material rather than being a completely new chemical from ground up. I hope that pharmaceutical companies would get interested in this new idea, study together, and take advantage of it.” He then concluded, “This research was something that I was personally attached to and took pride in. After having spent more than three years on this project, I am most proud of inventing an entirely new strategy that did not exist in the world before.”

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