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Keeping Copper Atoms Close: A New Strategy to Fight Superbugs

The compact arrangement of copper ions in a new copper-containing polymer can boost the decomposition of hydrogen peroxide and thus, the production of hydroxyl radicals to kill bacteria.

A looming health crisis that claims 700,000 lives per year and is projected to kill 10 million annually by 2050 takes shape in the form of antimicrobial resistance. Given its growing prevalence and severity, researchers have been exploring new ways to design antimicrobial drugs in hopes of re-sensitising superbugs and slowing down the rate of resistance. However, because the speed at which bacteria acquire antimicrobial resistance far outpaces drug discovery and development, the global pipeline of antimicrobials has been slow and scarce, leaving us to clamour for effective antimicrobials.

To tackle this problem, researchers at the Tokyo University of Science have devised a new approach to boost the in vivo antibacterial activity of hydrogen peroxide, a commonly used disinfectant, by using carefully tailored copper-containing polymers. Copper complexes are known to effectively catalyse redox reactions to produce reactive oxygen species like hydroxyl radicals that readily destroy biomolecules. In this case, Cu(I) works especially well to catalyse hydrogen peroxide decomposition to generate hydroxide anion and hydroxyl radicals, thus making copper an effective bactericidal agent. By catalysing this decomposition, Cu(I) is oxidised to Cu(II).

What makes this process interesting and potentially valuable is that hydrogen peroxide can, in turn, help to catalyse the reduction of Cu(II) back to Cu(I), thereby creating a perpetual cycle of catalysed reactions. However, this is only possible if the Cu(II)-containing complexes are close enough to one another, which is a difficult feat to accomplish. When Cu(II)-containing complexes are dissolved in a solution, the only way for them to come close together is by accidentally bumping into one another, and these accidental bumps are only likely if the solution is extremely concentrated with copper.

In the novel study led by Assistant Professor Shigehito Osawa and Professor Hidenori Otsuka, their team has found a way to overcome this obstacle. Borrowing knowledge from cellular chemistry, the team developed a long polymer chain and attached dipicolylamine, which acts as a copper-containing complex, on the backbone of the polymer. The dipicolylamine-copper complexes are collectively known as “pendant groups”.

When the polymers are dispersed in a solution, the Cu(II) in the pendant groups are kept within proximity to one another, thus resulting in locally high densities. This arrangement significantly increases the chances of two complexes coming into contact, thereby supporting the reduction of Cu(II) to Cu(I).

“In living organisms, copper forms complexes with proteins to efficiently catalyse redox reactions. For example, tyrosinase has two copper complex sites in close proximity to each other, which facilitates the formation of reaction intermediates between oxygen species and copper complexes. We thought we could leverage this type of mechanism in artificially produced polymers with copper complexes, even if dispersed in a solution,” explained Dr. Osawa.

To demonstrate the efficacy of their polymer, the team conducted a series of experiments and succeeded in showing that these tailored polymers can help to boost the catalytic splitting of hydrogen peroxide, thus increasing the production of hydroxyl radicals for lower concentrations of copper. When tested on bacterial cultures of Escherichia coli, the polymers were also found to greatly enhance the antibacterial potential of hydrogen peroxide.

Besides opening up a new path for designing antimicrobial drugs, the results of their study can also be applied to the food industry. “Because copper is an essential nutrient for living organisms, the antibacterial agent developed in this study holds promise as an efficient food preservative, which could contribute to increasing the variety of foods that can be preserved over long shelf times,” highlighted Dr. Osawa. [APBN]

Source: Osawa et al. (2021). Accelerated Redox Reaction of Hydrogen Peroxide by Employing Locally Concentrated State of Copper Catalysts on Polymer Chain. Macromolecular Rapid Communications, 2100274.