Novel approach offers a way to stop deadly infections without using antibiotics
In the next 25 years, more than 39 million people worldwide could die from antibiotic-resistant infections. With superbugs on the rise due to antibiotic misuse and overuse, researchers are searching for new ways to effectively fight bacterial infections to save lives.
Now, a multidisciplinary team of scientists led by UC Berkeley is working on a system that uses probiotics, beneficial bacteria within our bodies, and prebiotics, the nutrients that support these good bacteria, to suppress harmful bacteria. Funded by a $22.7 million award from the U.S. Department of Health and Human Services (HHS) through the Advanced Research Projects Agency for Health (ARPA-H), this work is part of the three-year Pro/Prebiotic Regulation for Optimized Treatment and Eradication of Clinical Threats (PROTECT) project.
Focusing on the lung microbiome, the researchers aim to identify probiotic strains that can combat Pseudomonas aeruginosa and Staphylococcus aureus — two deadly pathogens that often infect people with cystic fibrosis or pneumonia. Basically, they’re looking for good bacteria that are hungry for a fight.
“The concept is that we can assemble and differentially feed a set of natural ‘healthy’ lung microbes and cause them to essentially ‘eat the lunch’ of any invading pathogen,” said Adam Arkin, professor of bioengineering at UC Berkeley and lead principal investigator of the study. “That is, they literally eat all the metabolites that a pathogen needs to either establish itself or propagate in that environment.”
This unique approach, while more complex than trying to create a new broad-spectrum antibiotic, could potentially be used to combat antimicrobial-resistant infections in other areas of the body, such as wounds or the gut. It also has the power to change the way we treat and prevent bacterial infections in the future — and reduce our reliance on antibiotics.
Engineering the microbiome to combat pathogens
Arkin explained that bacteria in our bodies fit into three categories: passengers, friends or enemies. Those considered passengers simply hang out, do what they do, and don’t bother us. The friends help us digest food, moderate our immune system and protect us against pathogens. Then there are the enemies, the pathogens that can cause us harm.
He credits Kelsey Hern, a former Ph.D. student in his lab and now a postdoc at Northwestern University, with the idea of enabling good bacteria to outcompete bad bacteria. The principal investigator on the ARPA-H project, Hern describes the strategy as ecological rather than combative — more like crowding out weeds in a garden. By selectively feeding beneficial microbes, the team effectively closes the nutrient buffet that pathogens need to survive.
“Kelsey wondered if it were possible to build a self-supporting community that would actually want to live inside of us and that would provide a protective barrier against pathogens,” said Arkin. “And this led to her idea: How do you build a community that loves each other but eats the pathogen’s lunch?”
By analyzing the bacteria’s genome, Hern figured out how to select the right bacteria for the job: they needed to eat specific foods, so that they would compete against the targeted pathogen but not each other.
“We wanted to use our understanding of lung microbiome ecology to design communities that would work together to inhibit the pathogen,” said Hern. “Since the lungs have a pretty tightly controlled in-flow and out-flow of nutrients, we were able to model this ecology simply by measuring which lung nutrients the microbes can consume.”
To create a probiotic, researchers first take bacteria from healthy patients and assay them in a lab to check that they’re safe and to examine other characteristics. Then they put the bacteria in a media — an environment that simulates the lung. If researchers can demonstrate that the bacteria grow well together and compete with the pathogen, the bacteria will become the formulation for the probiotic.
As a final step in the ARPA-H project, the researchers place the probiotic in a nebulizer, like the type used by people with asthma, so the beneficial bacteria can be inhaled and delivered to the lung.
A multidisciplinary collaboration
Arkin explained that when the scientists were designing the ARPA-H project, they realized that expertise across disciplines would be needed to better understand how these engineered microbiomes operated once inside the body. A team of physicians, animal scientists, microbiologists and synthetic biologists came together to try to make this work.
“Our colleague, Karsten Zengler, was the expert that could give us a much better insight as to how these bacteria function in situ,” said Arkin. “He and his team at UC San Diego have developed these neat methodologies for peering deeply inside the cells as they operate in the lung. And you can see what systems are turning on to eat and to grow, for example.”
According to Arkin, the UC San Diego physician scientists provided a deeper understanding of what cystic fibrosis and pneumonia patients need and the pathogens that infect them. Together, the researchers worked to identify viable treatment methods and ways to properly test them in animal models.
Promising preliminary findings
Though the team’s findings are still preliminary, they are promising. “We’ve shown that if we put the bacteria colonies into mice, we can protect them from the pathogen,” said Arkin. “So it was a good, strong effect, however, not perfect.”
Not perfect because timing is everything. The person receiving the dose might not have the right food in their body at that moment for the good bacteria to feed on, preventing them from getting established.
The researchers have begun looking at ways to create a backpack of sorts for the bacteria, one loaded with enough food, or prebiotics, to help them survive until food becomes available in the recipient’s body.
“So we’re working on a way to increase the reliability of the treatment,” said Arkin. “We also realized that it’s not entirely clear how long these good bacteria persist in the body. In other words, what’s the dosing schedule?”
How long the engineered bacteria stay in the body depends on many factors, but one thing is certain: They are not going to stay there forever. The lung microbiome is in constant flux.
“It’s like being in an airport. You’re there, but sooner or later, you’re gone,” said Arkin. “So how often do you have to put them back? We’re looking at ways to determine that.”
Originally, the researchers thought that they had the perfect solution. The organisms make a molecule that can be detected in urine or breath, so one idea was to give the patient a breathalyzer to use, and, if the reading was low, they would know to redose. But there was a hitch.
“It turns out, doctors don’t like that because patients aren’t compliant; if you give them too many steps, they don’t do it right,” said Arkin. In addition, Hern noted that it isn’t easy to get a handheld mass spectrometer to measure one’s breath signal, though this may be possible in the future with some hardware advances. In the meantime, the researchers will continue to investigate simple methods for patients to gauge dosing needs.
Curbing our reliance on antibiotics
In many ways, this research presents a potential paradigm shift in our approach to fighting infection. “I think that there’s real power in this,” said Arkin. “Not just for this application in the lung, but for others.”
Arkin noted that his team is not the first to think of engineering the microbiome to fight infection. But, for many years, researchers have struggled to track the activity of these bacteria inside a living organism and observe their behavior over an extended period of time. Now, with recent advances in technology, researchers can take that next step.
“Our technologies for measurement have become better over the past decade and a half, so we’ve gained a much better understanding of how microbiomes operate in situ,” he said. “In addition, people have become more interested in taking a probiotic. So there are a lot of moving parts that can put us in good stead.”
Read this story on Berkeley Engineering.