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Fighting Antibiotic Resistance with a Little Help from Nature


Derek McMahon, Robert Lee, Ben Hariri, and Maureen Victoria.

The bacteria are winning. That’s what happens when they’re excessively attacked with the same antibiotics for 70 plus years. They get smarter and harder to defeat with the drugs.

And now here we are in 2017. About two million people became infected with resistant bacteria this year in the United States, and at least 23,000 of them died as a direct result, according to U.S. Centers for Disease Control and Prevention estimates. The future looks even grimmer: By 2050, resistant bugs will account for 10 million annual deaths around the world.

Thankfully, enough alarms have been sounded over the years to mobilize the research community to try and come up with new, potential solutions. There’s the more talked about approaches, like better drugs or gene editing technologies, but there’s also the less talked about – more natural – approaches that hold promise in this fight.

Researchers believe bacteria-fighting compounds in plants could be used, in some fashion, to help treat infections – and thus ween us away from the antibiotics.

For researchers in Penn’s departments of Otorhinolaryngology and Head and Neck Surgery, it started with the tongue. More specifically, the tiny receptors on the tongue that stand guard when bacteria – or fungus, viruses, or other particulates – enter our bodies. See, these bitter taste receptors, which are also in the nose and other parts around the body, not only detect bitter flavors, but they also defend us against unwanted bacteria, secreting compounds, such as nitric oxide, to kill them within minutes of their arrival.

So, can that taste-immunity connection be exploited to help battle infections? Robert J. Lee, PhD, an assistant professor of Otorhinolaryngology and Physiology, and Noam Cohen, MD, an associate professor of Otorhinolaryngology, are working to find out.

They first discovered that a bitter taste receptor known as T2R38 plays a role in people’s susceptibility to an infection known as chronic rhinosinusitis (CRS) – a disease that affects nearly 35 million Americans and is a huge driver of drug resistance. One out of five antibiotic prescriptions in the U.S. are for this condition.

People with a nonfunctioning receptor are called “non-tasters,” and more likely to get CRS, whereas people with a functioning receptor are called “supertasters,” and less likely to develop it. Essentially, with non-tasters, their taste receptors don’t do their job, and bacteria pass that first line of defense. (Check out this story in Scientific American from Lee and Cohen that takes a closer look into these “bodyguards.”)

The researchers are studying different ways to jumpstart receptors – 25 bitter tastes receptors are known to exist – to help destroy bacteria that enter the airway.

Here’s where the plants come in.

Plant compounds known as flavones have been shown to activate taste receptors, as well as possess anti-inflammatory and anti-bacterial effects. Researchers at Penn, including Benjamin M. Hariri, a former pre-med undergraduate researcher in Lee’s lab who is now at George Washington University School of Medicine, wanted to see how they would do up against the common sinus pathogens, Candida albicans, MRSA, and Pseudomonas aeruginosa.

They used several naturally-occurring flavones, including apigenin, chrysin, and wogonin, which are found in different types of plants and flowers, and tangeritin from citrus peels.

They reported in a recent study in PLoS ONE using human cells that the flavones not only killed a significant number of bacteria, but also had a synergy against them in the presence of antibiotics. They heightened the efficacy of the antimicrobials secreted by human airway cells, the body’s natural immune response, as well.

“We think that these compounds that activate the bitter taste receptors also activate defenses, and perhaps enhance them by directly acting on the bacteria,” Lee said. “If you’re using a compound that is not only activating nitric oxide production, but is also hurting the bacteria directly, it would make a lot sense to use that as a potential anti-bacterial therapy.”

He envisions dissolving the flavones in water in a high-volume rinse bottle that could be squirted up the nose or used in a Neti pot. Different plant extracts are on the market now, but Lee said most aren’t pure and contain other parts of the plant that are not soluble.

“This could be a first line therapy before people have to get to antibiotics. If they don’t get better, then you can respond with antibiotics,” Lee said. “Even eliminating that amount of antibiotic use is a huge deal when you are considering a quarter of adult antibiotic prescriptions are written for these types of infections.”

CRS infections also account for up to $10 billion dollars in direct health care costs. That number jumps to $20 to 30 billion when you consider all the people who lose productivity because of the infections, Lee said.

Next would be more studies to identify the specific flavone compounds that are the most effective and then testing them in humans, Lee said.

One trial already underway is a phase II clinical study led by Cohen that’s investigating the use of quinine, another natural product extracted from the bark of the cinchona tree, in CRS patients after undergoing surgery. Quinine has also been shown to activate bitter taste receptors.

“You get a lot of rampant antibiotic prescriptions for chronic rhinosinusitis, which is why we’re interested in understanding how the natural products function in the context of this specific disease. But all of this stuff is applicable to almost any sort of infection, especially in terms of what we are doing with taste receptors, because they are all over the body,” Lee said. “So, we think the work is broadly applicable, as well.”

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