Sarah explores the latest advances in Lyme disease treatment with Dr. Kim Lewis, a researcher, author, University Distinguished Professor and director of Antimicrobial Discovery Center at Northeastern University in Boston. He specializes in molecular science and is currently researching persister cells that lead to tolerance to antibiotics, uncultured bacteria of the environment and the microbiome and the search for new drugs. We’ll find out what role nature plays in all of this important work.
Chronic Lyme disease
Dr. Lewis became interested in studying Borrelia burgdorferi, the pathogen responsible for Lyme disease, when he realized that some people who had been treated for Lyme disease did not fully recover and went on to experience chronic Lyme disease.
Survival in the natural world
Dr. Lewis explains that most antibiotics come from soil microorganisms. For example, bacteria in micro fungi compete with each other using their natural antibiotics and we borrow these compounds to create antibiotics for human pathogens. One of the challenges in studying and developing these microbes is that only about 1% of these bacteria that grow in soil will also grow in a petri dish. Those that don’t easily grow in a petri dish are what Dr. Lewis refers to as “uncultured” or “microbial dark matter.”
“Most antibiotics that we currently have in the clinic come from soil microorganisms…bacteria in microfungi…(they) compete with each other and they fight out their differences with antibiotics. Then we borrow these compounds from them and use them to fight our pathogens.”Dr. Kim Lewis
Bringing nature into the lab
The problem of culturing bacteria dates back to the late 19th century. Since then, scientists have been experimenting with various culture media to grow soil bacteria in the lab. Lewis and his colleague Slava Epstein looked to microbes’ natural environment for a solution to the dark matter problem. They created a gadget called a diffusion chamber, where bacteria cells are sandwiched between two semipermeable membranes, keeping the cells inside and allowing small molecules to pass through. They placed this device in soil, where the bacteria are able to grow in full contact with molecules of their environment. After this “domestication” process, these microbes can then be transferred to a petri dish.
Broad spectrum antibiotics
One of the challenges with antibiotic treatment is that many antibiotics kill not only the intended pathogen, but also many of the helpful microorganisms in our body. As Dr. Lewis reminds us, antibiotics can wreck the microbiome. As we learn more about the critical role of a healthy microbiome, it becomes more important to protect these “symbionts”.
Protecting the microbiome
Dr. Lewis postulates that degradation of the microbiome may play a role in chronic Lyme. To test that hypothesis, Dr. Lewis and his colleagues set out to find an antibiotic that kills Borrelia but not the microbiome. They looked to nature, betting that nature would have a selective compound that would only kill spirochetes that live in the soil (such as Borrelia). They discovered that streptomyces hygroscopicus killed spirochetes, leading them back to an old “abandoned” antibiotic from 1953 called Hygromycin A. As it turns out, although this antibiotic had been abandoned because it showed poor activity against common microbes, it is very potent against spirochetes.
“We placed a bet on mother nature if you will, betting that nature would bother to evolve a compound that selectively kills spirochetes that live in the soil. Borrelia burgdorferi is a spirochete, a spiral shaped bacteria… Hygromycin A was discovered in 1953.”Dr. Kim Lewis
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Dr. Lewis points out that our own immune systems work along with antibiotics to kill bacterial infections. He points out that biofilms protect bacteria by covering these cells with a slime-like exopolymer. Under the microscope, this “slime” contains columns and channels for liquid and nutrients. Antibiotics are unable to kill all cells because some bacteria cells are dormant, resisting the action of antibiotics. Dr. Lewis notes that it is these persister cells within biofilm that make infection difficult to treat.
Dr. Lewis tells us that a small portion of cells, including our own cells and bacterial cells, become dormant when the genes that make them active are “turned off”. When bacterial cells are dormant, they can’t be killed by certain antibiotics. When antibiotic concentration drops, these dormant cells reactivate and become susceptible to being killed by antibiotics. He notes that it’s very difficult to detect the pathogen in chronic Lyme, so difficult to determine the role of persister cells or degradation of the microbiome. He points out that chronic Lyme often looks like autoimmune disease, with symptoms that are very similar to those of long COVID.
“Persister cells… go into dormancy… (and there is a) low probability random event we call molecular noise…cell where a gene – that gene was of – that cell goes into temporary dormancy – while it sent into dormancy antibiotics cannot kill it because antibiotics kill active cells – you get this small population of cells that survive the hit of antibiotics… you get a difficult to treat relapsing infection.”Dr. Kim Lewis
Dr. Lewis recalls the discovery of acyldepsipeptide, a compound that kills active and dormant cells of staphylococcus bacteria. The search is on for a similar compound that will work for both active and dormant forms of Borrelia burgdorferi. Dr. Lewis describes the concept of pulse dosing, where dormant cells are allowed to become active and are killed with antibiotics before they are able to proliferate. He notes that active and dormant Borrelia, when studied in test tubes, are killed by repeated pulse dosing with standard antibiotics.
Nematodes and their microbiome
Dr. Lewis and his colleagues wondered whether there existed bacteria on earth that have the same requirement for antibiotics that we do. They would have to be nontoxic, effective against nasty pathogens, and systemically available. It turns out that nematodes and humans require these features for antibiotics. They found a group of symbionts in the microbiome of nematodes (little worms that live in the earth). By studying compounds that nematodes use to fend off bacteria, Dr. Lewis and his colleagues found compounds for human use called darobactins. Thank you Dr. Lewis for searching for new and better antibiotics to treat Lyme disease. We look forward to hearing more about your important work in the future!
“One of the very difficult issues in chronic Lyme is that we cannot detect the pathogen in patients with chronic lyme. We cannot culture it or identify it by other methods, so whether it’s there or not, we do not know. It’s possible that some cells are hiding somewhere, but it’s also possible that the pathogen, and treatment with broad spectrum antibiotics have wrecked the immune system, and now you are getting something that looks like an autoimmune disease or long Covid… the symptoms are very very similar to the symptoms of chronic Lyme”Dr. Kim Lewis
- Kim Lewis, University Distinguished Professor
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- A New Antibiotic Has Been Hiding in the Gut of a Tiny Worm. It May Be Our Best Weapon Against Drug-resistant Bacteria.