About 23,000 Americans and 25,000 Europeans die each year from antibiotic-resistant infections, according to the US Centers for Disease Control and Prevention (CDC). The trajectory is even more alarming: the number of infections is expected to quintuple roughly every eight years. If current trends continue, infections will be the world’s leading cause of death by 2040. That demands a change in the way health practitioners tackle bacteria that cause infections. Antibiotics have been the weapon of choice for decades, but as bacterial resistance grows, more imaginative approaches are required.
One of the key problems with antibiotics is that most bacteria carry the modifications needed to overcome any particular antibiotic in their cellular DNA. When it is exposed to antibiotics, a bacterium shuffles its DNA like a deck of cards, until it comes up with a combination that works against the antibiotics. And the odds are stacked in bacteria’s favour. “You've got billions of bacteria inside of you,” explains Vincent Rotello, a chemist at the University of Massachusetts. ”You're going to have a decent number of them getting a full house.” When that happens, you’ve got an antibiotic-resistant strain.
Rather than focussing on new antibiotics, Rotello is developing bacteria-resistant materials that would prevent most bacteria from hitching a ride on their surfaces, while killing the few that do. These materials could coat everything from clothes, to money, paint and even the medical devices implanted in our bodies to replace our worn-out knees or hips. And they just might save our lives.
Side-stepping evolution
The first step is to develop a new class of biological coatings that are resistant to adhesion, which would make it far harder for bacteria to spread from one place or person to another. Rotello is adapting nonstick surfaces like Teflon and fluorinated polymers, and metallic films like titanium, to use on fibers and other materials. “Much of the technology is already here, but implementation is challenging,” says Rotello. “We can Teflon-coat fibers, but the resulting fabric can be quite uncomfortable and expensive. Folks are working on it, though.”
An even bigger challenge is finding coatings that can be used on medical devices and implants that go inside the human body, to make them safe and non-toxic. In his lab, Rotello has been working on a different type of film based on the proteins in our blood serum that keep blood cells from aggregating. The same could be used to prevent bacteria from sticking to a surface. And since these films are based on proteins, the process would not involve introducing potentially toxic materials into the body. “Biological systems like proteins and cells use seemingly random patterns of positive and negative charge to limit interactions.” says Rotello. “This same design feature can be used by scientists to create surfaces that bacteria have difficulty adhering to.”
Stick-resistant surfaces alone, however, are not likely to work well enough to completely prevent infections. “Bacteria have this nasty ability to reproduce, so if only one or a few bacteria stick to a surface they will multiply, eventually creating an infection,” says Rotello. In medical implants, the survival of just a couple of stray microbes on the surface of a bacteria-resistant knee or hip replacement can lead to infections causing months of pain, or even death. “It is difficult or impossible to create surfaces that are completely and perfectly non-adherent to bacteria,” he says. “So a plan B that focuses on killing bacteria is definitely needed.”
The trick is to find ways of killing bacteria without harming humans. In his lab, Rotello has homed in on one of the key differences between our human cells and bacteria. The surface of bacterial cells has a much denser negative charge than that of mammalian cells. This makes sense from an evolutionary perspective. Negative cells repel other negatively charged cells, and bacteria thrive by dispersing, dividing and conquering — so the homogeneity of their charge drives them apart. Mammalian cells, on the other hand, live together, and thus contain a greater mix of positive and negative charges in their membranes.
For more than a decade and a half, Rotello has been developing gold nanoparticle scaffolds that can hold other molecules of his choosing. To combat bacteria, he’s designed a series of gold, positively-charged, nanoparticles that exert a powerful pull on the bacteria. The scaffold is curved, and the charged molecules are spaced out in such a way that when they attract a bacterium, they gradually pull and stretch the cell wall until it splits. “Many antibiotics interfere with a bacterium’s ability to form its cell walls,” he explains. “These particles are different. They basically rip the cell wall apart.”
But not all bacterial infections remain as individual cells. Some of the most difficult-to-treat infections involve biofilms — colonies of bacteria within an extracellular shielding matrix that allows them to outwait antibiotics. Biofilms are highly resistant to antibiotics.
To overcome biofilms, Rotello has developed the equivalent of a microscopic guided missile that penetrates the biofilm and, once inside, delivers a payload that destroys the bacteria. For the payload, he takes advantage of an evolutionary adaptation of plants, which use natural oils to fight bacteria. The oils are able to penetrate the bacteria’s cell membrane and in the process rip them apart. But the oil doesn’t work against biofilms on its own. It just sits on top, prevented from reaching the bacteria inside.
To penetrate the biofilm shield, Rotello encases a droplet of peppermint oil in a sponge-shaped polymer-nanoparticle carrier. The ‘sponge’ is positively charged, and has a unique mixture of shape, density and flexibility that allows it to gradually work through a biofilm, pulled by the negative charge of bacteria on the other side. Once the sponge penetrates the biofilm, it releases the peppermint oil, which destroys the bacteria.
Rotello’s approaches to fighting infections are still in the early stages of development, but he’s confident that in a few years they will yield effective tools to prevent and combat bacterial infections, and provide complementary strategies to antibiotics.
