The new combined drug therapy gives hope for the treatment of chronic wound infections

Researchers at the University of Oregon have tested a new associated healing therapy that can dismantle bacteria difficult to treat chronic wound infections.

Their discoveries, published on September 29 in the journal, illuminate ways to develop more effective antimicrobial treatment that promote healing in chronic wounds. Such treatments can also help reduce the risk of severe infections that sometimes lead to amputation, such as diabetic foot ulcers.

Financially financed by the National Institutes of Health, the approach uses long -known substances that do not do much against themselves against the difficult to treat to the treatment of aluminum chronic wounds, namely pseudomonas Aeruginosa bacteria. But by adding small doses of a simple molecule called chloran to standard antibiotics, the combination turned out to be 10,000 times more effective in killing bacterial cells in a laboratory than one -way antibiotics. This type of strength reduced the dose of drugs required to kill P. Aeruginos.

If the findings can be translated into people, they can help shorten the time at which patients must take antibiotics and reduce the risk of toxicity, said Melanie Spero, an assistant professor at UO College of Arts and Sciences and the senior author of the study.

Although examined here in the context of chronic wound infections, the strategy can promise the problem of the problem Antibiotics resistance wider.

I think that drug combinations will be a critical approach that will help us fight the development of antibiotic resistance. Finding examples of synergy among antimicrobials that are already on the market will be really valuable. And we will have to delve into the mechanisms why they work well with each other. ”

Melanie Spero, Biology assistant professor at UO College of Arts and Sciences

Challenges in the treatment of chronic wound infections

A chronic wound is a wounded tissue that did not start to treat in normal time frames from four to 12 weeks. Diabetes is the most common type, said Spero, which is an open graying on the bottom of the foot, which is made of poor circulation, long -lasting pressure and lack of feeling.

According to research published by the American Diabetes Association, about 1 out of 4 People with type 2 diabetes Develop a feet ulcer, and more than half of these cases are infected.

“Active infection is the most common complication that prevents healing and closing the wound,” said Spero, adding that when heavy, 1 on 5 diabetic ulcers require amputation. “This is very devastating, but many microbiology studies have not been carried out in this area. So this is an opportunity to make a big difference.”

Shifts of blood flow, high demand for oxygen inflammatory cells and the presence of bacteria in a chronic place of the wound limit how much oxygen reaches the tissue, preventing healing. These low oxygen conditions are also a problem that makes bacterial infections difficult to fight: it exposes antibiotic resistance and tolerance.

When the place of the wound becomes limited by oxygen, bacteria switch to energy breathing to energy, called nitrate breathing. Their growth slows down without oxygen, but they still survive and continue to spread.

The slow growth of bacteria, especially P. Aeruginosa, makes them notoriously tolerant of conventional antibiotics. This is because many drugs are assessed on the basis of how well -growing bacteria kill well, he said spero. But if the bacteria grow slowly, those antibiotics, which are often tested only in oxygen -rich conditions, become ineffective, she said.

At least after serving alone, he found a spero.

Obtaining a larger course from current antibiotics

When antibiotics are combined with a small molecule called chloran, “emphasizes the bacterial cell in a way that makes it very susceptible to antibiotics,” said Spero.

Research is based on spero tests for the first time conducted as a PhD student at the California Institute of Technology. Earlier, she discovered that Chlooran, a simple compound that is harmless to mammals and people in low doses used in her research, turns antibiotics from summer performers into strong bacterial killers in cellular cultures and diabetic mouse models.

Thanks to a subsidy of $ 1.84 million in five years from the National Institutes of Health, Spero was able to continue working in her new laboratory at the UO. Her latest study shows that Chlooran works for all kinds of antibiotics more effective in killing P. Aeruginos and can reduce the dose of antibiotics needed to fight the pathogen. Studies have shown that with a small amount of chlooran in the mix it could use 1 percent of the standard dose of a wide spectrum antibiotic.

“In the case of chronic infections, people often deal with antibiotics for a long time, and this can sow havoc on the body,” said Spero. “Drugs with high toxicity can interfere with intestinal microorganisms and have serious side effects. Everything we can do to shorten the time that a person will be on antibiotics and lower the dose, the better.”

The results come from controlled laboratory tests on bacterial cell farms, so translation to the clinic is still far away. Especially since chronic infections usually do not cover a single bacteria, said spero because they organize entire microbiological districts living and interacted. She added that the discovery of how drug combinations affect these complex communities in model organisms is an obvious next step.

The exact mechanism of how Chlooran strengthens antibiotics is also still a secret. Spero explained that Chlooran scientists are known to kidnap nitrate breathing, so with a completely lack of oxygen, the microbes are erased. But in microenviska with low or high levels of oxygen, bacteria can somehow repair damage and tolerate the chemical. Spero said that in traditional unidirectional shows, which are usually performed in conditions with high oxygen, Chlooran was overlooked.

“I think we underestimate this: the types of stress impose these compounds on a cell that is invisible to us,” she said. “If our only measure is vitality – whether the bacteria have died or died? – that’s all we are looking for. We must ask what processes are pushed out or stressed in a cell that can lead to its fall in the presence of antibiotics.”

Spero hopes that looking “under the hood” of a cell during the exposure to chloran-antibiotics will show scientists a biological machinery of how bacteria will become susceptible to a series of antibiotics.

“It will have important implications not only in the treatment of chronic wound infections, but also broadly for the field of infectious diseases and our fight against resistance to antibiotics and treatment failure,” said Spero. “When we understand the mechanisms of drug synergy, we can start finding other molecules that cause these synergistic behavior, and this will not seem to guess in which we test every possible combination of medicines. We can start making rational design of medicines, using particles that have already been approved.”