New Type of Drug Kills Antibiotic-Resistant Bacteria

Researchers at IBM are designing nanoparticles that kill bacteria by poking holes in them. The scientists hope that the microbes are less likely to develop resistance to this type of drug, which means it could be used to combat the emerging problem of antibiotic resistance. This type of drug has not had much success in clinical trials in the past, but initial tests of the nanoparticles in animals are promising.

 Nano killer: This drug-resistant staph bacterium has been split open and destroyed by an antimicrobial nanoparticle.

Drug-resistant bacteria have become a major problem. In 2005, nearly 95,000 people in the United States developed a life-threatening staph infection resistant to multiple antibiotics, according to the U.S. Centers for Disease Control and Prevention. It takes just one to two decades for microbes to develop resistance to traditional antibiotics that target a particular metabolic pathway inside the cell, says Mary B. Chan-Park, professor of chemical and biological engineering at Nanyang Technological University in Singapore, who was not involved with the research. In contrast, drugs that compromise microbes' cell membranes are believed to be less likely, or slower, to evoke resistance, she says.

"We're trying to generate polymers that interact with microbes in a very different way than traditional antibiotics," says James Hedrick, a materials scientist at IBM's Almaden Lab in San Jose, California. To do this, Hedrick's research group took advantage of past work on a library of polymer building blocks that can be mixed and matched to make complex nanoparticles. To make a nanoparticle that would selectively attack bacterial membranes and then break down harmlessly inside the body, the IBM group put together three types of building blocks. At the center of the polymer sequence is a backbone element that's water-soluble and tailored to interact with bacterial membranes. At either end of the backbone is a hydrophobic sequence. When a small amount of these polymer chains are added to water, the differences between the ends and the middle of the sequence drive the polymers to self-assemble into spherical nanoparticles whose shell is entirely made up of the part that will interact with bacterial cells. This work is described this week in the journal Nature Chemistry.

IBM's labs aren't equipped for biological tests, so the researchers collaborated with Yi Yan Yang at the Singapore Institute of Bioengineering and Nanotechnology to test the nanoparticles. They found that the nanoparticles could burst open and kill gram-positive bacteria, a large class of microbes that includes drug-resistant staph. The nanoparticles also killed fungi. Other types of deadly bacteria that have different types of cell membranes would not be vulnerable to these nanoparticles, but the IBM researchers say they are developing nanoparticles that can target these bacteria, too, though it is more difficult. "Through molecular tailoring," says Robert Allen, senior manager of materials chemistry at IBM Almaden, "we can do all sorts of things"—designing particles with a particular shape, charge, water solubility, or other property.

The IBM researchers believe the drug could be injected intravenously to treat people with life-threatening infections. Or it could be made into a gel that could be applied to wounds to treat or prevent infection.

However, Chan-Park cautions, other drugs that work by this membrane-piercing mechanism have not been very successful so far. Those that have shown early promise on the lab bench either were toxic to animal cells or simply didn't work in the complex environment of the human body.

More tests will be needed to say definitively whether the nanoparticles are safe and will work in people. Initial tests of the IBM particles with human blood cells and in live mice have been promising. Allen says the nanoparticles didn't interact with human blood cells because their electrical charge is significantly greater than that of bacterial cells. There were no signs of toxicity in mice injected with the particles, and none of them died. 

In addition to developing nanoparticles that can attack other types of bacteria, the IBM group is working on making larger quantities of the designer polymers, scaling up from the current two-gram capacity to the kilogram quantities needed for larger clinical tests. IBM won't be getting into the pharmaceutical business, says Allen, but the company plans to partner with a healthcare company to license the polymer drugs.

By Katherine Bourzac
From Technology Review

Posted in: BIOMEDICINE