Traditional antibiotics like doxycyclin and vancomycin—the kind that many bacteria can now resist because of their overuse—work by getting inside the bacterial cell and interfering with essential cellular processes. Charged peptides have been proposed as alternatives, since they work by electrostatically interacting with the negatively charged bacterial cell wall, poking holes in the bacterial cell membrane and thereby killing the bacteria. Because these molecules physically disrupt the bacterial membrane rather than target an intracellular component, bacteria are less able to develop resistance.

However, these agents are expensive to produce, have short circulating half-lives in the body, and tend to kill red blood cells in addition to bacteria. They have thus met with limited clinical success. A report in this week’s Nature Chemistry describes the synthesis of the first biodegradable antimicrobial polymer nanoparticles to help fill the breach.

An example of the charged peptides is magainin, named from the Hebrew word for shield, magain. It was isolated from frogs after an observant researcher noticed that the frogs, kept for other studies, never got infected after they were operated on and then stuck back into their grimy tanks.

But charged peptides like magainin can be difficult to work with. Charged polymers have proven to be preferable to peptides because their manufacture is easier and cheaper to scale up, and because they are less haemolytic—they are better at killing bacteria than they are at killing red blood cells. But the fact that they are not biodegradable poses a problem when it comes to their use in humans.

Nederberg et al. made charged polymers out of cyclic carbonates, which are nontoxic and biodegradable. Their degradation produces alcohol and carbon dioxide, and they degrade slowly, so they have prolonged antimicrobial functions inside the body and long shelf-lives outside of it. Because of their amphiphilic nature—they have a positively charged region, which is hydrophilic, but also a hydrophobic region—these nanoparticles spontaneously form small spheres in water, so they can hide their hydrophobic parts inside.

The enhanced charge of the spheres allows them to more efficiently bind to the bacterial cell wall than other antimicrobial polymers that act as single molecules. The nanostructures were effective against Gram-positive bacteria, methicillin-resistant Staphylococcus aureus (MRSA), and the fungus Cryptococcus neoformans, and had an efficiency comparable to that of conventional antimicrobials at their best, all while leaving red blood cells alone.

When injected into mice, the antimicrobial nanoparticles did not exhibit any significant toxicity over the test period, which lasted for fourteen days. It's not yet exactly the nanotechnological immunomodulation described by Neal Stephenson in The Diamond Age but it's getting close.

Nature Chemistry, 2011. DOI: 10.1038/NCHEM.1012 (About DOIs).

Listing image by LLNL