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Antibiotics have proved to be a valuable weapon in the fight against infection, but their popularity has also become their undoing. Although the drugs cripple harmful microbes from within, bacteria that survive such sabotage tend to develop resistance that makes them even more dangerous. To counter this, a team of researchers led by IBM Research–Almaden in San Jose, Calif., and Singapore's Institute of Bioengineering and Nanotechnology are developing a technique that enlists polymer-based nanoparticles to supplement antibiotics by destroying bacteria protective membranes, ensuring that their morphing days are through. Just as important, upon completing their mission these nanoassassins would biodegrade harmlessly within the body.
Drug resistance develops in part because conventional antibiotics such as ciprofloxacin and doxycycline do not physically damage a microbe's cell wall. Instead, they enter their target less disruptively and move on to disrupt the DNA within or block cell division or trigger cellular self-destruction. Strains that survive this assault, however, can evolve to defend themselves against future attacks, opening the door for deadlier versions of bacteria such as methicillin-resistant Staphylococcus aureus(MRSA), which killed nearly 19,000 Americans in 2005 (the last year for which the U.S. Centers for Disease Control has comprehensive data).
In addition, the high doses of antibiotics needed to kill such an infection indiscriminately destroy healthy red blood cells in addition to contaminated ones.
"This whole issue of emerging resistance of antibiotics is going to be a huge problem in the foreseeable future," says James Hedrick, the IBM Research advanced organic materials scientist who led the study, published April 4 in Nature Chemistry (Scientific American is part of Nature Publishing Group). "I think we can start to see it now with the number of infections, associated deaths and health care costs."
Hedrick and his colleagues propose a tandem that deploys biodegradable nanostructures—perhaps injected directly into the body or applied topically to treat skin infections—made of a polycarbonate polymer that could help finish the job started by antibiotics. Once these polymers, which are 200 nanometers across, come into contact with water inside the body or on the skin, they would self assemble into a new polymer structure designed to target bacteria-infected cells and lyse (disintegrate) their cell membranes and walls.
These nanoparticles distinguish between healthy cells and bacteria-infected cells by the electric charges each produces. "The [electric] charge of these bacterial membranes is significantly higher than that of a healthy cell," Hedrick says. "We just tune the charge of the nanoparticle to selectively go after the dangerous microbe."
In the researchers' in vitro testing they determined that even at levels 10-fold or higher than the normal dosing level, there is no rupturing of red blood cells, says Alan Louie, research director of IDC Health Insights, a Framingham, Mass.,–based consulting firm. Louie, who is familiar with but did not participate in the study, notes the importance of being able to "tune" the nanoparticles so that they stay in the body long enough to do their job without accumulating in internal organs.
Whereas other nanomaterials have been proposed to transport drugs in the body or fight disease, the polycarbonate polymers that Hedrick's team is studying would later be broken down by enzymes in the body and thus less likely to accumulate. "After a short period of time they revert back to an innocuous by-product with a very low molecular weight that can easily be removed from the body," he adds.
The researchers' next step is to broaden the types of bacteria that their nanoparticles can destroy. Right now, they are tuned to attack so-called "gram-positive" bacteria such as MRSA, yeast and fungi. Hedrick wants to create a more universal ally to antibiotics that can likewise target gram-negative bacteria such as Esherichia coli and salmonella. "What makes gram-negative bacteria so tricky is that you have a much more complex membrane that surrounds the microbe," Hedrick says. "We're beginning to understand how to navigate and disrupt those membranes."
Other areas of study include tinkering with nanoparticles' shape (a more elongated design could more easily navigate the body) and materials that have a lower molecular weight but pack the same punch.
"Clearly, there's a lot of work ahead, particularly in validating the safety in humans and determining an appropriate vehicle to be able to deliver the nanoparticles into the human body," Louie says. Yet in addition to the direction Hedrick outlined, Louie sees a lot of potential to nanoparticles' ability to self assemble, creating a structure that could someday deliver medicine into the body and play an even bigger role in health care.
