Posted in: Chemistry, Healthcare, IBM Research-Almaden, Publications

A new molecule designed to kill deadly, drug-resistant superbugs

In 2016, I had a bacterial infection that I acquired after a routine knee surgery. Fortunately, my immune system reacted favorably to antibiotics, but had the bacteria been a “superbug,” resistant to medication, my story might have had a different ending.

This incident inspired me to focus my work on discovering a new solution. With Singapore’s Institute of Bioengineering and Nanotechnology (IBN) of the Agency for Science, Technology and Research (A*STAR), my team and I at 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. The findings were just published in the scientific journal Nature Communications.

Superbugs that are resistant to antibiotics are a serious health threat. According to the UK Review on Antimicrobial Resistance[1], superbugs kill around 700,000 people worldwide each year. 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.

Clearly, 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.

By 2050, it is estimated that 10 million people could die each year if existing antibiotics continue to lose their effectiveness.

To address these challenges, 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 multidrug-resistant bacteria. It is biodegradable and no significant toxicity to human cells has been detected.

The polymer kills bacteria in the following way. First, 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.

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. [Credit: Institute of Bioengineering and Nanotechnology]

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. [Credit: Institute of Bioengineering and Nanotechnology]

Testing the top five multi-drug resistant bacteria

The team tested the polymers on mice infected with five hard-to-treat multi-drug resistant bacteria: Acinetobacter baumannii, E. coli, Klebsiella pneumoniae, methicillin-resistant Staphylococcus aureu and Pseudomonas aeruginosa.  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: peritonitis (an infection of the stomach’s inner lining) and lung infections from Pseudomonas aeruginosa. The polymers eliminated the bacterial infections in both groups of mice with negligible toxicity.

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 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.

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, (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. [Credit: Institute of Bioengineering and Nanotechnology]

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, (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. [Credit: Institute of Bioengineering and Nanotechnology]

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. In 2016, we demonstrated the efficacy of synthetic polymers to combat deadly viral diseases. As viruses and bacteria contribute to the majority of infectious diseases, this new study rounds out our ability to someday treat a spectrum of infectious diseases with a single, new type of mechanism without the onset of resistance.

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

IBN and IBM are now seeking collaborations with pharmaceutical companies to help develop the polymers into an antimicrobial treatment for actual use.

[1] “Tackling Drug-Resistant Infections Globally: Final Report and Recommendations.” The Review on Antimicrobial Resistance, May 2016.

Distinguished Research Staff Member, IBM Research – Almaden, San Jose, California

James Hedrick

Distinguished Research Staff Member, IBM Research – Almaden, San Jose, California