A Charged Partnership: Unlikely Partners In The Antibiotics Arms Race

Antibiotic resistance is a growing threat to global health. By combining their expertise, a cancer drug delivery researcher and a technology giant might just have come up with a solution to prevent the slide into a post-antibiotic era.

AsianScientist (Jun. 8, 2015) – The discovery of antibiotics in the mid 20th century revolutionized the practice of medicine, not only making it possible to treat infectious diseases but also opening up new modes of medical intervention. Without antibiotics, procedures such as chemotherapy, organ transplantation and even relatively simple hip replacement surgery could not take place, as the risk of infection would be too great. In the pre-antibiotic era, the average human life span was about 50 years. Today, we enjoy a dramatic increase in life span and quality of life, in no small part due to the affordable and readily available antibiotics that we take for granted.

However, antibiotics are turning into a victim of their own success. Antibiotics are available over the counter in certain countries, which has led to indiscriminate use. Furthermore, the unrestrained use of antibiotics in livestock has resulted in their accumulation in environmental runoff. Under this immense selection pressure, microbes have launched their own counter-attack, evolving in response to heavy antibiotic use and rendering many drugs ineffective.

To make matters worse, there are currently few antimicrobial drugs in the pipeline. Pharmaceutical companies, many of which built their companies on antibiotics in the early days, have been driven by market incentives to more profitable drugs. However, an information technology company has now stepped in where pharmaceutical companies have fled.

In close partnership with the Institute of Bioengineering and Nanotechnology (IBN) in Singapore, technology giant International Business Machines, more famously known as IBM, has developed a radically new approach to antimicrobials. But how did a company known for thinking machines and semiconductor technology start its very own nanomedicine program?

When serendipity knocks

Dr. Yang Yi Yan, group leader at IBN, is a key piece of that puzzle. Widely known for her contributions to cancer research in both nanoparticle targeting of cancer and drug delivery, her group had begun to extend their focus to antimicrobial applications for their polymers and were looking for new synthesis methods.

“At the end of 2004, I was invited to a polymer conference in Australia. This was where I first met James Hedrick from IBM, who was giving a plenary talk,” Yang told Asian Scientist Magazine.

Dr. James Hedrick is IBM Research’s lead scientist for the advanced organic materials group. At the time, IBM researchers were exploring new ways to etch silicon wafers used in semiconductors and had identified a new kind of polymer that produces an electrostatic charge when chained together. Yang, who is also an adjunct associate professor with the Department of Pharmacy at the National University of Singapore, thought these materials could also be used in medicine.

Dr. Yang Yi Yan from the Institute of Bioengineering and Nanotechnology. Credit: IBN.
Dr. Yang Yi Yan from the Institute of Bioengineering and Nanotechnology. Credit: IBN.

“I thought to myself: why do they use these polymers for electronics when they are very good candidates for drug delivery, especially as a carrier? When I spoke with to him about this, he seemed quite interested and we ended up talking for a long time about a possible research collaboration,” Yang related.

This chance encounter at a conference led to a joint study agreement between IBN and IBM, beginning in 2007. IBM provided the expertise in synthetic methodology, while Yang’s group at IBN supplied the bioengineering expertise.

“We knew which functional groups were required for loading the drug molecules, as well as what was needed for polymer stability in vivo. In this collaboration, we discussed the functionality of polymers and designed the polymer system together.

“People who work in drug delivery are normally bioengineers. They are trained in a certain field but may not have expertise in another. It’s quite important to work with people with different expertise who can complement each other,” she said.

Ninja polymers mimic natural antimicrobial peptides

The fruitful partnership has led to a slew of research publications, 20 patents and most importantly, a useful new antimicrobial that might just stop the tide of antibiotic resistance. Nicknamed ‘ninja polymers,’ the synthetic polymers bind to microbial cell walls and cause the cell membrane to become leaky, killing the bacteria in the process.

“Traditional antibiotics are small molecules that target specific bacterial proteins or genes, leaving the bacterial cell membrane intact,” Yang explained.

“In contrast, natural antimicrobial peptides (AMPs) work by disrupting the bacterial cell wall. Even though they are highly effective, AMPs have limited applications because of their non-specific damage to host cells, poor stability, short half-life in vivo and high manufacturing cost.

“Our synthetic antimicrobial polymers mimic AMPs. They are cationic (positively charged) and so are attracted to the negatively charged bacterial cell wall, while their hydrophobic (water-avoiding) components insert themselves into the membrane to avoid the aqueous environment.”

As this quick killing mechanism is destructive to the cell membrane—a bacterial structure that is relatively slow-evolving, bacteria die before they are able to develop drug resistance.

“We tested our antimicrobial polymer side-by-side with antibiotics and we saw that the efficacy of antibiotics was reduced after multiple exposures. The efficacy of our polymer, however, did not change, even over 20 exposures. We tested our polymer on many multi-drug resistant strains which were isolated from clinical samples,” Yang said.

The Yang-Hedrick work on antimicrobial polymers was published in the journals Nature Chemistry in 2011 and Nature Communications in 2013. Yang foresees that their research could have a wide range of applications that would be of particular interest to consumer care companies.

This article was first published in the print version of Asian Scientist Magazine, Jul 2014.


Photo: Global Panorama/Flickr/CC.

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Rebecca did her PhD at the National University of Singapore where she studied how macrophages integrate multiple signals from the toll-like receptor system. She was formerly the editor-in-chief of Asian Scientist Magazine.

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