The antibiotic that takes the bite out of Lyme
Study shows specific antibiotic cures Lyme disease at a fraction of the dosage
Northwestern University
- Current ‘gold standard’ treatment does not work for up to 20% of population and kills beneficial bacteria
- Scientists screened nearly 500 FDA-approved compounds to assess effectiveness against Lyme
- Piperacillin effectively treats Lyme disease at 100-times lower dose than doxycycline
CHICAGO --- 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. Even in acute cases, Lyme can be devastating; but early treatment with antibiotics can prevent chronic symptoms like heart and neurological problems and arthritis from developing.
Scientists from Northwestern University have 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, the current gold standard treatment. At such a low dose, piperacillin also had the added benefit of “having virtually no impact on resident gut microbes,” according to the study, which will be published April 23 in the journal Science Translational Medicine.
Doxycycline and other generic antibiotics, on the other hand, wreak havoc on the microbiome, killing beneficial bacteria in the gut and causing troubling side effects even as it kills the borrelia 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.
“Powerful, broad-spectrum antibiotics that kill extracellular bacteria are seen as the most effective medication because physicians want to just kill the bacterium and don't care how,” said Brandon L. Jutras, who led the research. “This is certainly a reasonable approach, but 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 other fail. The more we understand about the various strains and species of Lyme disease-causing Borrelia, the closer we get to a custom approach.”
Jutras is an associate professor in the microbiology-immunology department of Northwestern University Feinberg School of Medicine, and a member of Northwestern’s Center for Human Immunobiology. Jutras’s lab was recently named a Phase 3 winner in LymeX Diagnostics, the Steven & Alexandra Cohen Foundation’s $10 million competition to accelerate the development of Lyme disease diagnostics, and in 2021 he won the Bay Area Lyme Foundation Emerging Leader Award.
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, in which someone potentially exposed to Lyme (with a known deer tick bite) would receive a single-dose shot of the medication.
To reach the conclusion that the penicillin relative would be the most effective and targeted treatment, 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.
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.
Historically, piperacillin has been administered as part of a two-drug cocktail to treat severe strep infections because strep can break down beta-lactams (piperacillin’s class of antibiotics) unless accompanied by tazobactam, which is an inhibitor of the enzyme that inactivates piperacillin. Jutras wondered if using the same two medications, rather than piperacillin alone, would be a more effective bacteria killer.
“Bacteria are clever,” Jutras said. “Strep and some other bacteria combat antibiotics by secreting beta-lactamases that inactivate piperacillin. We found the approach is totally irrelevant in the context of Lyme disease and another way that makes piperacillin more specific. Adding the beta-lactamase inhibitor doesn’t improve the therapy because Lyme Borrelia don’t produce beta-lactamase, but the cocktail does negatively impact the microbiome by becoming more broadly functional against beneficial residents.”
Lyme prevention 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.
The study was supported by the Bay Area Lyme Foundation and United States Department of Agriculture (VA-160113), the Dennis Dean Research Grant (Virginia Tech), the National Institutes of Allergy and Infectious Disease (R01AI173256, R01AI178711), the Steven & Alexandra Cohen Foundation and the Global Lyme Alliance.
Journal
Science Translational Medicine
Post-treatment Lyme disease syndrome may be driven by remnants of infection
Researchers learn why the body may continue to respond to an invisible threat long after bacterial death
Northwestern University
- Up to 20% of patients treated for Lyme experience persistent symptoms
- Lyme’s post-infection features share some similarities to long COVID-19 and could be due to lingering antigens
- Individual differences in immune response to remnants of the Lyme bacterium’s cell wall likely play an important role in patient outcome.
CHICAGO --- 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.
Now, Northwestern University scientists believe they know what causes the treated infection to mimic chronic illness: the body may be responding to remnants of the Borrelia burgdorferi (the bacteria that causes Lyme) 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, said bacteriologist Brandon L. Jutras.
“Lyme and long COVID-19 are clearly vastly different diseases, but it’s possible that they share a more general mechanism of inappropriate inflammation caused by remnants of a previous infection,” said Jutras, who led the research. “The maladaptive response is a product of an infection, but perhaps not necessarily an active one in all cases.”
Peptidoglycan is a structural feature of virtually all bacterial cells and a common target of antibiotics, including penicillin. The research, to be published April 23 in the journal Science Translational Medicine, tracked the biodistribution of peptidoglycan from different bacteria, in real time, and found that all cell wall material is rapidly shed, but Lyme disease’s peptidoglycan persists for weeks to months.
Lyme arthritis is one of the more common long-term impacts of exposure to Lyme. If a patient has a swollen knee, for instance, it is full of synovial fluid, a natural lubricant found in joints. Jutras said his team looked at the fluid in humans and found that pieces of the peptidoglycan were omnipresent weeks to months after treatment.
“In the context of Lyme arthritis, if you give patients anti-inflammatory, disease-modifying antirheumatic drugs, they get better,” Jutras said. “Some of these very same patients do not get better after oral and IV antibiotics, which implies there is something unique about how patients respond at a genetic level.”
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, beginning in graduate school, and was previously an associate professor at Virginia Tech University.
“Peptidoglycan is kind of like a structural skeleton in virtually all bacteria, acting as a big protective bag for the bacterium,” Jutras said. “Penicillin and amoxicillin and dozens of other drugs target peptidoglycan synthesis because it’s a molecule that is specific to bacteria, it has similar structural features across the kingdom, and it’s essential.”
Lyme’s peptidoglycan, however, 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.”
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, including weaponizing monoclonal antibodies to target peptidoglycan for destruction.
The research was supported by the National Institutes of Allergy and Infectious Diseases (R21AI159800, R01AI173256, R01AI178711), the Steven & Alexandra Cohen Foundation, the Department of Defense (TB220039), the Global Lyme Alliance and the Bay Area Lyme Foundation.
Journal
Science Translational Medicine
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