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A by-product of papermaking helps kill bacteria while avoiding antibiotic resistance

Lignin customized with positively charged chains offers a fresh way to treat infections without fear of rapid-onset microbial resistance

by Benjamin Plackett, special to C&EN
September 1, 2021

A schematic of a strand of lignin with a positively charged chain of dimethylaminoethyl methacrylate attached to it.
Lignin, modified at its hydroxyl groups to include positively charged polymer chains (red), can attach itself to bacterial membranes and then pull the membrane apart.

Deaths from infectious disease have plummeted by 70% since antibiotics were first introduced in the 1940s, according to the Wellcome Trust. But bacteria are constantly fighting back by mutating their DNA and finding new ways to evade once-useful medicines. A new study proposes an alternative tactic to traditional antibiotics that could avoid promoting this resistance: tearing apart bacterial membranes with chemically modified lignin, a bountiful and cheap by-product of paper production (ACS Biomater. Sci. Eng. 2021, DOI: 10.1021/acsbiomaterials.1c00856).

Synthetic polymers have shown promise as antibacterials because they’re able to undermine entire cell membranes, rather than attacking more specific targets that are easier for bacteria to evolve defense mechanisms against. However, they often come with biocompatibility issues, such as toxicity or unwanted inflammatory and immune responses.

By contrast, lignin—a highly branched, oxygen-containing plant biopolymer consisting chiefly of phenols—has been praised in previous studies for its biocompatibility potential. This was one of reasons that Rajamani Lakshminarayanan of the National University of Singapore and Dan Kai and Xian Jun Loh of the Institute of Materials Research and Engineering decided to see if they could use lignin to fight bacterial infections.

“The real advantage of our technique is the lack of resistance developed by the bacteria we tested it on,” Lakshminarayanan says.

The researchers built off of lignin’s hydroxyl groups to add positively charged polymer chains, which are pulled toward and dig into negatively charged phosphate groups on a bacterium’s outer membrane. Simultaneously, hydrophobic groups within lignin are repelled by the cell membrane. When these two interactions happen simultaneously, the polymer rips holes in the membrane, killing the bacteria.

The researchers tested the polymer by applying it to the corneas of rabbits that were infected with Pseudomonas aeruginosa to simulate keratitis, a common eye infection in humans often caused by wearing contact lenses for too long. The results showed that the lignin-based polymers could eradicate the bacteria within 72 h.

The researchers also ran experiments to assess whether two strains of Escherichia coli could evolve resistance to the novel treatment. Even after 20 rounds of exposure, the dose of the polymer needed to prevent visible growth of the bacteria did not increase, implying that the bacteria developed little resistance. When the experiments were conducted instead with the antibiotic polymyxin B, the results were significantly different. By the 18th round of exposure, one of the E. coli strains required a 128-fold increase of the antibiotic to restrict its visible growth, and the other needed a two-fold increase.

This impressed Orlin D. Velev, a biomolecular engineer at North Carolina State University. “It’s going to be very difficult for bacteria to develop resistance to this because they’d have to recharge their whole membrane so the polymer doesn’t bind, and that’s a lot for bacteria to have to do.”

While the study’s findings prove that the polymer is effective when applied topically, the scientists aim to develop it as an oral or intravenous drug, thereby broadening the types of infections it could fight. “It’s probably not toxic in systemic use,” Kai says. “But we’d need a lot more evidence before we could be sure of that.”


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