Spider peptides battle superbugs and cancer

As antibiotic resistance rises and fears over superbugs grow, scientists are looking for new treatment options. One area of focus is antimicrobial peptides (AMPs), which could someday be an alternative to currently prescribed antibiotics, many of which are becoming increasingly useless against some bacteria. Now, a team reports in ACS Chemical Biology that they have improved the antimicrobial — and anticancer — properties of an AMP from a spider.

According to the U.S. Centers for Disease Control and Prevention, 2 million people become infected with antibiotic-resistant bacteria in the U.S. each year. Because no known antibiotics work against these bacteria, patients simply have to hope that their natural defenses eventually overcome the infection. But some patients experience severe symptoms, landing them in a hospital, and in extreme cases, they could die. Researchers are trying to find alternatives to traditional antibiotics, and one such possibility is a group of peptides called AMPs. These peptides are found in all plants and animals as a type of immune response and have been shown to be potent antibiotics in the laboratory. Gomesin, an AMP from the Brazilian spider Acanthoscurria gomesiana can function as an antibiotic, but it also has anticancer activity. When gomesin was synthesized as a circle instead of as a linear structure, these characteristics were enhanced. Sónia Troeira Henriques and colleagues wanted to further boost the peptide’s traits.

The team made several variations of the cyclic gomesin peptide and found that some of these were 10 times better at killing most bacteria than the previously reported cyclic form. In other experiments, the new AMPs specifically killed melanoma and leukemia cells, but not breast, gastric, cervical or epithelial cancer cells. The researchers determined that the modified peptides killed bacteria and cancer cells in a similar way — by disrupting the cells’ membranes. The group also notes that the modified AMPs were non-toxic to healthy blood cells.

Regenerative bandage heals diabetic wounds faster

At some point in their lives, 15 percent of people with diabetes will develop a painful and hard-to-treat foot ulcer. Twenty-four percent of those affected will require a lower-leg amputation because of it. And, in some instances, what seems like a harmless sore might even lead to death.

A Northwestern University team has developed a new treatment for this severe and potentially deadly complication of diabetes. Called a “regenerative bandage,” the novel material heals diabetic wounds four times faster than a standard bandage and has the added benefit of promoting healing without side effects.

“Foot ulcers cause many serious problems for diabetic patients,” said Guillermo Ameer, professor of biomedical engineering in Northwestern’s McCormick School of Engineering and surgery in the Feinberg School of Medicine. “Some sores don’t heal fast enough and are prone to infection. We thought that we could use some of our work in biomaterials for medical applications and controlled drug release to help heal those wounds.”

An expert in biomaterials and tissue engineering, Ameer’s research was published online last week in the Journal of Controlled Release. Yunxiao Zhu, a PhD student in Ameer’s laboratory, is the paper’s first author. Northwestern Engineering’s Hao F. Zhang, associate professor of biomedical engineering, and Feinberg’s Robert Galliano, associate professor of surgery, also contributed to the work.

Diabetes can cause nerve damage that leads to numbness in the feet. A diabetic person might experience something as simple as a blister or small scrape that goes unnoticed and untreated because they cannot feel it to know that its there. As high glucose also thickens capillary walls, blood circulation slows, making it more difficult for these wounds to heal. It’s a perfect storm for a small nick to become a life-threatening sore.

Some promising treatments for these chronic wounds exist, but they are costly and can come with significant side effects. One gel, for example, contains a growth factor that has been reported to increase cancer risk with overuse.

“It should not be acceptable for patients who are trying to heal an open sore to have to deal with an increased risk of cancer due to treating the wound,” Ameer said.

Ameer’s laboratory previously created a thermo-responsive material — with intrinsic antioxidant properties to counter inflammation — that is able to deliver therapeutic cells and proteins. His team used this material to slowly release into the wound a protein that hastens the body’s ability to repair itself by recruiting stem cells to the wound and creating new blood vessels to increase blood circulation.

“We incorporated a protein that our body naturally uses to attract repair cells to an injury site,” Ameer said. “When the protein is secreted, progenitor cells or stem cells come to the wound and make blood vessels, which is part of the repair process.”

The thermo-responsive material is applied to the wound bed as a liquid and solidifies into a gel when exposed to body temperature. When the same amount of the protein was directly applied all at once, no benefit was observed. This demonstrates the importance of slow release from the thermo-responsive material. Ameer believes that the inherent antioxidant properties within the material also reduce oxidative stress to help the wound heal.

“The ability of the material to reversibly go from liquid to solid with temperature changes protects the wound,” Ameer said. “Patients have to change the wound dressing often, which can rip off healing tissue and re-injure the site. Our material conforms to the shape and dimensions of the wound and can be rinsed off with cooled saline, if needed. This material characteristic can protect the regenerating tissue during dressing changes.”

In collaboration with Zhang, Ameer imaged diabetic wounds to discover that they were much healthier after application of the regenerative bandage. The blood flow to the wound was significantly higher than in those without Ameer’s bandage.

“The repair process is impaired in people with diabetes,” Ameer said. “By mimicking the repair process that happens in a healthy body, we have demonstrated a promising new way to treat diabetic wounds.”

When it comes to developing stem cell treatments, seeing is half the battle

Stem cell therapies hold great promise in treating a variety of diseases, but in order to develop them researchers must first be able to monitor them inside the body. Enter the contrast agent.

“Often things go wrong right away when stem or therapeutic cells are injected into the body because some cells can migrate, while other dying cells are eaten by the body and expelled,” says Xiao-an Zhang, an assistant professor of chemistry at U of T Scarborough.

“It’s important to know if these cells are being injected in the right place, where they go once inside the body and whether they’re still alive. The only way to do that is with an effective contrast agent.”

Conventional contrast agents are directly injected into the body to make some tissues or diseases more clearly visible on MRI scans. The one developed by Zhang and his team, including Ph.D. student Inga Haedicke, U of T Assistant Professor Hai-Ling Margaret Cheng and two research groups (Dr. Timothy Scholl and Dr. Paula Foster) from Western University, can improve monitoring at the cellular level, which is a crucial element in measuring the effectiveness of stem and therapeutic cell treatments.

While still early in development, stem and therapeutic cells may one day offer effective treatments against diseases, particularly cancer. But one major hurdle in developing these treatments is an inability to effectively monitor them once inside the body.

“Current MRI methods are not great at looking at what’s going on at the cell or sub-cellular level. It’s just not powerful enough – the resolution and sensitivity needs to be higher and the contrast needs to be greater in order to distinguish one type of cell from another,” says Zhang.

“Traditional MRI can’t do quite what we need it to do right now, but there’s huge opportunity to improve the technology.”

Magnetic resonance imaging (MRI) uses a magnetic field and radio waves to produce a detailed image of tissues within the body. MRI is ideal for medical imaging because it’s milder than techniques like CT scans or X-rays since it’s not as invasive and does not rely on ionizing radiation.

There are quite a few technical challenges when developing an effective contrasting agent for cellular imaging. For one, it needs to be non-toxic or low in toxicity so it doesn’t damage cells. It also needs to be able to enter cells and accumulate in order to provide a clear enough contrast from the rest of objects in the image, notes Zhang.

The agent developed by Zhang and his team addresses these challenges by using manganese porphyrin. Manganese is a micronutrient that the body’s cells can handle and forms a very stable complex with the porphyrin, a type of pigment molecule that can help to achieve the necessary properties. Using a new porphyrin developed by Haedicke, the agent can be delivered to cells more efficiently in smaller concentrations and can accumulate more effectively than current alternatives.

“The real positive aspect of this design is that it’s cell permeable, and that the new mechanism allows it to stay inside the cell and accumulate,” says Haedicke. “This is extremely important for labelling which cells are being monitored.”

The research, which will be published in the journal Chemical Science, received funding from the Canada Foundation for Innovation (CFI) and the Natural Sciences and Engineering Research Council of Canada (NSERC).

The next steps for Zhang and his team is to focus mostly on using the agent on different types of stem cells and to test them in vivo.