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Polycarbonate Molecule Kills Superbugs

Fight against Antibiotic-Resistant Infections

Superbugs that are resistant to antibiotics are a serious health threat. By 2050, it is estimated that 10 million people could die each year if existing antibiotics continue to lose their effectiveness. The situation has become more acute because bacteria are starting to develop resistance to the last-line antibiotics, which are typically given only to patients infected with bacteria resistant to generally available antibiotics. The medical community needs more choices in treating these patients. While research on synthetic polymers for these purposes exists, challenges such as toxicity, non-biodegradability or limited ability to target multiple bacteria strains have arisen.

Researchers from Singapore’s Institute of Bioengineering and Nanotechnology (IBN) of the Agency for Science, Technology and Research (A*STAR) and the IBM Research – Almaden lab in Silicon Valley developed a synthetic molecule designed to kill five deadly types of multidrug-resistant bacteria with limited side effects. This new material could potentially be developed into an antimicrobial drug to help treat patients with antibiotic-resistant infections.

Four-step killing mechanism of the polymer against drug-resistant superbugs (Step 1) Binding of the positively charged polymer to the bacteria cell surface, (Step 2) Neutralizing the positive charges of the polymer to enter the bacterial cell membrane, (Step 3) Penetrating into the bacterial cyotoplasm, a fluid that fills the cell, and (Step 4) Precipitating the cytoplasmic substances to kill the bacterium (© Institute of Bioengineering and Nanotechnology)

Dr Yi Yan Yang from IBN brought together a multidisciplinary research team from the United States, China, and Singapore to develop a new class of antimicrobial polymers called guanidinium-functionalized polycarbonates with a unique mechanism that can target a broad range of multi-drug-resistant bacteria. It is biodegradable and no significant toxicity to human cells has been detected. The polymer binds specifically to the bacterial cell. Then, the polymer is transported across the bacterial cell membrane into the cytoplasm, where it causes precipitation of the cell contents (proteins and genes), resulting in cell death.

Fighting the Top Five Multi-Drug-Resistant Bacteria

The team tested the polymers on mice infected with five hard-to-treat multi-drug resistant bacteria. These superbugs are commonly acquired by hospital patients, and can cause systemic infections that lead to septic shock and multiple-organ failure. The results showed that the bacteria were effectively removed from the mice and no toxicity was observed. The researchers then further tested the effectiveness of the polymers on mice with two types of systemic infections caused by superbugs (an infection of the stomach’s inner lining and lung infections). The polymers eliminated the bacterial infections in both groups of mice with negligible toxicity.

Normal cells of the Acinetobacter baumannii bacteria before (left) and after (right) treatment with the polymers. Image on right showed that the cytoplasmic substances within the bacterial cell membrane have precipitated, killing the bacteria (Institute of Bioengineering and Nanotechnology)

To determine whether the bacteria will develop any resistance to the polymer, the team collaborated with Dr. Paola De Sessions at the Genomic Institute of Singapore of A*STAR, and with the Cell Engineering team of Dr. Simone Bianco and James L. Hedrick at IBM Research – Almaden to perform genomic analysis. They found that the bacteria did not show any resistance development even after multiple treatments with the polymer.

The findings were published in the scientific journal Nature Communications. The study illustrates the potential for this new field the researchers denote as “macromolecular therapeutics” to create entirely new classes of treatments for multiple diseases. IBN and IBM are now seeking collaborations with pharmaceutical companies to help develop the polymers into an antimicrobial treatment for actual use.


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