6 March 2018

New molecule could tackle hard-to-treat infections

Source: IBN. A diagram of the four-step killing mechanism of the polymer against drug-resistant superbugs.
Step 1: Binding of the positively-charged polymer to the bacteria cell surface;
2: Neutralising the positive charges of the polymer to enter the bacterial cell membrane,
3: Penetrating into the bacterial cyotoplasm, a fluid that fills the cell, and
4: Precipitating the cytoplasmic substances to kill the bacterium.

An international research team led by Singapore's Institute of Bioengineering and Nanotechnology (IBN) of the Agency for Science, Technology and Research (A*STAR) and IBM Research have developed a synthetic molecule that can kill five deadly types of multidrug-resistant bacteria. Similar solutions tend to have bad side effects but this molecule has limited, if any, side effects, the researchers said.

The new material could be developed into an antimicrobial drug to treat patients with antibiotic-resistant infections. The finding was reported* in Nature Communications.

According to the UK Review on Antimicrobial Resistance, superbugs kill around 700,000 people worldwide each year. By 2050, 10 million people could die each year if existing antibiotics continue to lose their effectiveness, as is expected to happen. 

“There is an urgent global need for new antimicrobials that are effective against superbugs. The situation has become more acute because bacteria are starting to develop resistance to the last-line antibiotics, which are given only to patients infected with bacteria resistant to available antibiotics,” said Professor Jackie Ying, Executive Director of IBN.

The research community is developing alternatives to antibiotics using synthetic polymers. However, the antimicrobial polymers developed so far are either too toxic for clinical use, not biodegradable or can only target one type of bacteria.

To address this problem, Dr Yi Yan Yang from IBN brought together a multidisciplinary research team from the US, China and Singapore to develop a new class of antimicrobial polymers called guanidinium-functionalised polycarbonates. These polymers have a unique killing mechanism that can target a broad range of multidrug-resistant bacteria. They are also biodegradable and non-toxic to human cells.

The polymer kills bacteria by entering the bacterial cell, which is not normally possible. First, the polymer binds specifically (piggybacks) to the bacterial cell. This allows the polymer to be transported across the bacterial cell membrane into the cell contents, where it causes precipitation (creation of solids from the liquid) of the cell contents (proteins and genes), killing the cell.

The team tested the polymers on mice infected with five hard-to-treat multidrug-resistant bacteria: Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae, methicillin-resistant Staphylococcus aureu (MRSA) and Pseudomonas aeruginosa. These superbugs can be found in hospitals and can lead to septic shock and multiple organ failure.

The tests showed that the bacteria were effectively removed from the mice, and no toxicity - negative side effects - was observed. The researchers then further tested the effectiveness of the polymers on mice with two types of bacterial infections caused by superbugs: peritonitis, an often-fatal infection of the stomach’s inner lining, and lung infections from Pseudomonas aeruginosa. The polymers eliminated the infections in both groups of mice with negligible toxicity.

Dr Yi Yan Yang, Group Leader at IBN said, “We have demonstrated the first example of a biodegradable synthetic macromolecule with broad-spectrum antimicrobial activity in mice, unique killing mechanism and no toxicity. Once the polymer finishes its job of killing the bacteria, it will be naturally degraded after three days and will not remain in the body. This antimicrobial agent shows great promise for the treatment and prevention of multidrug-resistant systemic infections.”

 “This study illustrates the potential for this new research field we denote as ‘macromolecular therapeutics’ to create entirely new classes of treatments for multiple diseases,” said Dr James Hedrick, Distinguished Research Staff Member, IBM Research – Almaden, San Jose, California in the US. “In 2016, we demonstrated the efficacy of synthetic polymers to combat deadly viral diseases. The current research for treating bacterial infections rounds out our ability to someday treat a spectrum of infectious diseases with a single, new type of mechanism without the onset of resistance.”

To determine whether the bacteria will develop any resistance to the polymer, the team collaborated with Dr Paola Florez de Sessions at A*STAR’s Genome Institute of Singapore and the Cell Engineering group of Dr Simone Bianco 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.

This study was also done in collaboration with the University of North Dakota’s School of Medicine and Health Sciences, and the First Affiliated Hospital of Zhejiang University’s College of Medicine.

IBN and IBM are now seeking collaborations with pharmaceutical companies to develop the polymers into a commercial treatment.

The Institute of Bioengineering and Nanotechnology (IBN) is the world’s first bioengineering and nanotechnology research institute. Established in 2003, IBN aims to improve healthcare and quality of life.

*Willy Chin, Guansheng Zhong, Qinqin Pu, Chuan Yang, Weiyang Lou, Paola Florez de Sessions, Balamurugan Periaswamy, Ashlynn Lee, Zhen Chang Liang, Xin Ding, Shujun Gao, Collins Wenhan Chu, Simone Bianco, Chang Bao, Yen Wah Tong, Weimin Fan, Min Wu, James L. Hedrick and Yi Yan Yang, A Macromolecular Approach to Eradicate Multidrug Resistant Bacterial Infections While Mitigating Drug Resistance Onset, Nature Communications, 9 (2018) 917.