The physician and microbiologist Alexander Fleming was best known for discovering the world’s first broadly effective antibiotic: penicillin. In his Nobel Prize acceptance speech, however, he warned that this was not a permanent solution—the overuse of penicillin would likely lead to bacterial resistance.
Fleming was right; nearly a century later, the World Health Organization (WHO) has declared antibiotic resistance among today’s greatest threats to global health. Antimicrobial polymers, or AMPs are part of a growing arsenal of weapons that scientists are developing to fight back. These polymers can be designed as alternatives to antibiotics, launching multipronged attacks against pathogens, while minimizing the threat of drug resistance.
In collaboration with researchers at the IBM Almaden Research Center, a team led by Yi Yan Yang, Covering Executive Director at the A*STAR’s Institute of Bioengineering and Bioimaging (IBB), set out to explore new approaches for developing next-generation AMPs. Copolymers—polymers with two or more functionalized groups—were seen as particularly promising, given their ability to eliminate bacteria via multiple pathways. Copolymers of quaternary ammonium- and guanidinium-functionalized groups, for example, destroy bacterial cell walls while simultaneously precipitating bacterial proteins.
“[Unlike antibiotics] our antimicrobial polymers avoid the risk of developing resistance because they kill bacteria through physical methods,” explained Yang. “This is difficult to gain resistance to because the polymers target larger and more essential components required for the bacteria to exist.”
Using a biodegradable polycarbonate previously developed by the team as a backbone, the researchers attached functionalized groups in either a blocked or random molecular arrangement. They then tested the efficacy of these copolymers using a checkerboard microdilution assay, a technique used to determine the effect of combining polymers on inhibiting bacterial growth. The random copolymer configuration outperformed the block arrangement as a potent bacteria killer. However, in an unexpected result, both these copolymers worked just as effectively as homopolymers with only a guanidinium functionalized group.
“This was a learning point for us that having both cationic groups on the same molecule might hinder the ability of one of the functional groups,” said Eunice Leong, study first author and Senior Research Fellow at IBB. To circumvent this problem, the team added functional groups on separate polycarbonate backbones thus creating two distinct homopolymers.
In a breakthrough result, this combination of two homopolymers demonstrated powerful synergistic killing effects in some drug-resistant bacterial strains and additive effects in others, killing about 99% of the microorganisms in each case. Notably, this approach proved to be significantly more potent, greatly reducing the minimum inhibitory concentration, or the lowest amount of the antimicrobial needed to prevent the growth of microorganisms.
Follow-up studies are now aimed at validating their findings on the 2-in-1 homopolymer formulation in a mouse model of bacterial infection.
The A*STAR-affiliated researchers contributing to this research are from Institute of Bioengineering and Bioimaging (IBB).
