Taking the bite out of Lyme disease

Lyme disease, a disease transmitted when deer ticks feed on infected animals like deer and rodents, and then bite humans, impacts nearly half a million individuals in the U.S. annually. Lyme can be devastating; but early treatment with antibiotics can prevent chronic symptoms like heart and neurological problems and arthritis from developing. 

What’s new

In two new studies led by bacteriologist Brandon L. Jutras, Northwestern scientists have identified an antibiotic that cures Lyme disease at a fraction of the dosage of the current “gold standard” treatment and discovered what may cause a treated infection to mimic chronic illness in patients. The studies were published in the journal Science Translational Medicine.

Jutras, who joined Northwestern faculty last summer, is an associate professor of microbiology-immunology at Northwestern University Feinberg School of Medicine and a member of the Center for Human Immunobiology at Northwestern. He has been studying Lyme disease for more than 15 years.

Besting the gold standard

The antibiotic doxycycline is the current gold standard treatment for Lyme. However, doxycycline and other generic antibiotics, wreak havoc on the microbiome, killing beneficial bacteria in the gut and causing troubling side effects even as it kills Borrelia burgdorferi, the bacteria that causes Lyme. In addition to its negative impact on the gut, doxycycline also fails to help between 10 and 20% of individuals who take it, and it is not approved for use in young children — who are at the highest risk of tick bites, and therefore, of developing Lyme.

More effective, or at least more specified, treatment options are needed as climate change extends tick seasons and Lyme becomes more prevalent.

Northwestern scientists identified that piperacillin, an antibiotic in the same class as penicillin, effectively cured mice of Lyme disease at 100-times less than the effective dose of doxycycline. At such a low dose, piperacillin also had the added benefit of “having virtually no impact on resident gut microbes,” according to the study.

The team screened nearly 500 medicines in a drug library, using a molecular framework to understand potential interactions between antibiotics and the Borrelia bacteria. Once the group had a short list of potentials, they performed additional physiological, cellular and molecular tests to identify compounds that did not impact other bacteria.

The authors argue that piperacillin, which has already been FDA-approved as a safe treatment for pneumonia, could also be a candidate for preemptive interventions for those potentially exposed to Lyme (with a known deer tick bite).

They found that piperacillin exclusively interfered with the unusual cell wall synthesis pattern common to Lyme bacteria, preventing the bacteria from growing or dividing and ultimately leading to its death.

Understanding when Lyme lingers

Symptoms that persist long after Lyme disease is treated are not uncommon — a 2022 study found that 14% of patients who were diagnosed and treated early with antibiotic therapy would still develop Post Treatment Lyme Disease (PTLD). Yet doctors puzzle over the condition’s causes and how to help their patients through symptoms ranging from severe fatigue and cognitive challenges to body pain and arthritis.

Northwestern scientists believe they now know what causes the treated infection to mimic chronic illness: The body may be responding to remnants of the Borrelia cell wall which breaks down during treatment yet lingers in the liver. (This matches one theory behind the underlying causes of long COVID-19, in that persisting viral molecules may encourage a strong, albeit unnecessary, immune response, according to Jutras.)

In another new study, researchers tracked the biodistribution of peptidoglycan, a structural feature of virtually all bacterial cells and a common target of antibiotics, from different bacteria. They found that Lyme disease’s peptidoglycan persists for weeks to months.

Lyme’s peptidoglycan is structurally unique, and this difference may be behind its persistence in humans. Instead of looking the same as with other bacteria, the Lyme peptidoglycan is fundamentally distinct, which is facilitated in part by sucking up sugars from its tick vector. Upon bacterial cell death — by antibiotics or the immune system — surviving molecules tend to relocate to the liver, which can’t process the modified peptidoglycan. Without this modification, it seems likely that the peptidoglycan would clear right away, as in other infections.

“The unusual chemical properties of Borrelia peptidoglycan promote persistence, but it’s the individual patient response to the molecule that likely impacts the overall clinical outcome,” Jutras said. “Some patients will have a more robust or stronger immune response, which could result in a worse disease outcome, while the immune system of others may largely ignore the molecule. So, in essence, it’s not about whether the molecule is there or not, it’s more about how an individual responds to it.”

What’s next

Jutras hopes the groundbreaking findings will lead to development of more accurate tests, possibly for PTLD patients, and refined treatment options when antibiotics have failed. To effectively stymie PTLD, instead of neutralizing an infection that may no longer exist, efforts are underway to neutralize the inflammatory molecule.

Lyme prevention also remains a challenge — no approved human vaccine exists — and Jutras hopes his research moving forward will help with developing proactive strategies to diagnose and treat it.

“I think the future for Lyme disease patients is bright in that we are approaching an era of customized medicine, and we can potentially create a particular drug, or a combination to treat Lyme disease when others fail,” Jutras said. “The more we understand about the various strains and species of Lyme disease-causing Borrelia, the closer we get to a custom approach.”