New drug treatments for Lyme disease are emerging as potential breakthroughs in combating persistent Borrelia burgdorferi infections, which are resistant to standard antibiotics like doxycycline and amoxicillin. These persistent bacterial forms are often linked to Post-Treatment Lyme Disease Syndrome (PTLDS), a condition that affects 10-20% of patients, leaving them with ongoing symptoms like fatigue, joint pain, and neurological issues. Recent research highlights a number of promising drugs from an FDA-approved drug library that show greater efficacy in targeting these difficult-to-treat bacteria. By exploring alternatives to traditional antibiotics, these new treatments could offer significant hope for improving recovery and providing relief to chronic Lyme disease sufferers who have struggled with long-term symptoms.
New Drug Treatments for Persistent Lyme Disease Infections
Lyme disease, caused by the bacterium Borrelia burgdorferi, is a tick-borne illness affecting hundreds of thousands of people annually in the United States and Europe. While early-stage Lyme disease can often be successfully treated with a few weeks of antibiotics like doxycycline or amoxicillin, not everyone recovers fully. In fact, 10%–20% of patients experience lingering symptoms, such as chronic fatigue, joint pain, and cognitive difficulties, even months after the initial antibiotic treatment. This condition is known as Post-Treatment Lyme Disease Syndrome (PTLDS), and there is growing evidence that the continued presence of persister forms of Borrelia burgdorferi—which standard antibiotics fail to kill—may be responsible.
In a study published in Antibiotics (Basel), a research team led by Jie Feng, Megan Weitner, Wanliang Shi, Shuo Zhang, David Sullivan, and Ying Zhang explored the effectiveness of various drugs from an FDA-approved drug library in targeting these persisters. Their work represents an important step toward finding better treatments for Lyme disease, particularly for patients who suffer from persistent symptoms long after receiving standard antibiotic therapy.
What Makes Lyme Disease So Persistent?
Most antibiotics are designed to kill bacteria when they are actively growing. However, Borrelia burgdorferi can exist in different forms, including a non-growing, dormant state called the stationary phase. Bacteria in this phase are much harder to kill because they become resistant to many antibiotics. The bacteria can also form biofilms—protective structures that shield them from the immune system and antibiotics.
Researchers believe that these dormant, persistent forms of B. burgdorferi may be responsible for the chronic symptoms seen in PTLDS patients. These persisters evade destruction by traditional antibiotics, leading to ongoing infection that is difficult to detect and treat. This study aimed to find drugs that could target these stubborn persisters more effectively than the antibiotics currently used to treat Lyme disease.
Screening a Library of Drugs for Anti-Persister Activity
The team screened a variety of drugs from an FDA-approved drug library to see which ones were more effective at killing Borrelia burgdorferi persisters than the standard Lyme disease antibiotics, such as doxycycline and amoxicillin. The drugs were tested on seven-day-old stationary phase cultures of the bacteria, which mimic the persistent forms that can evade treatment.
The researchers used an approach involving both microscopy and a special assay (SYBR Green I/Propidium Iodide) to count how many bacterial cells were alive or dead after drug treatment. By analyzing the reduction in live bacteria, they could determine how effective each drug was at killing persisters.
Promising Findings: A Diverse Range of Drugs Shows Effectiveness
The screening revealed 113 drug hits that were more effective at killing Borrelia persisters than the currently prescribed Lyme antibiotics. These drugs came from a variety of categories, including antibiotics, antifungals, antivirals, and even drugs used for conditions other than infections, such as macular degeneration or cancer treatment.
Among the most promising drugs identified were:
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Daptomycin: This antibiotic, often used to treat severe bacterial infections, stood out as one of the most effective drugs in killing Borrelia persisters. It reduced the percentage of live bacteria to just 35%, compared to 75% or more survival with standard Lyme antibiotics.
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Verteporfin: Typically used to treat macular degeneration, this drug showed strong activity, killing more than 73% of persisters. It works by producing reactive oxygen species (ROS) when activated, which can damage bacterial cells and membranes.
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3-Formyl Rifamycin: Part of the rifamycin family of antibiotics, this drug reduced persister viability by 59%. Rifamycins are known for their ability to penetrate bacterial cells, making them useful against difficult-to-treat infections.
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Tartar Emetic: Traditionally used as an antiparasitic, tartar emetic killed about 55% of the persisters. Though not suitable for internal use in humans due to toxicity, it provides clues on how certain mechanisms might be exploited to develop safer treatments.
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Toltrazuril: An antiprotozoal drug, toltrazuril was highly effective, killing 57% of the bacteria. This suggests that drugs used for other parasitic infections may offer potential in Lyme disease treatment.
Other drugs that showed substantial activity include fluconazole (an antifungal), zanamivir (an antiviral used to treat influenza), and mepartricin (another antifungal). These drugs, which were not originally designed to target Borrelia, may still hold promise for future Lyme disease therapies.
A Closer Look at Key Drug Categories
Antibiotics and Antimicrobials
While antibiotics like doxycycline and amoxicillin remain the standard treatment for Lyme disease, their limitations in targeting persisters have driven the search for alternatives. In this study, several antibiotics were found to be more effective against persisters than the drugs currently used in clinical practice. For example, daptomycin and 3-formyl rifamycin showed substantial activity, killing a significant portion of the bacteria in their dormant state.
In addition, some broad-spectrum antibiotics, such as sarafloxacin and clinafloxacin (types of quinolones), demonstrated potential as alternative treatments, though further research is needed to confirm their effectiveness in real-world settings.
Antifungal and Antiviral Agents
Interestingly, many drugs not traditionally used for bacterial infections also showed promise. For example, the antifungal fluconazole, commonly prescribed for fungal infections like yeast infections, was found to kill 45% of persister cells. Likewise, antiviral drugs such as zanamivir (used for influenza) were unexpectedly effective against Borrelia, reducing viable cells by more than 50%.
These findings suggest that drugs targeting different types of pathogens—fungi, viruses, or parasites—could have applications in treating bacterial infections like Lyme disease, especially when it comes to tackling persistent forms of bacteria.
Drugs for Non-Infectious Conditions
One of the most striking findings from this study is that several drugs used to treat non-infectious conditions showed high activity against Borrelia burgdorferi persisters. For example, verteporfin, which is used in ophthalmology for treating macular degeneration, was found to kill nearly three-quarters of the dormant bacteria. This drug works by producing reactive oxygen species (ROS) when exposed to light, which damages cell membranes and causes cell death.
Similarly, oltipraz, an anticancer agent, and dextrorphan tartrate, a drug used to treat coughs and other non-infectious ailments, were also effective against persisters. These drugs are involved in the glutathione/γ-glutamyl pathway, a mechanism that protects cells from oxidative stress. By interfering with this pathway, these drugs may make bacteria more vulnerable to ROS-induced damage, leading to cell death.
What Do These Findings Mean for Lyme Disease Treatment?
The discovery of 113 drugs with high activity against persisters opens the door to new possibilities for treating Lyme disease, especially for patients who continue to experience symptoms after standard antibiotic therapy. The study highlights the need for drug combinations that target bacteria in different ways, particularly by disrupting their cell membranes, energy production, and ability to protect themselves from oxidative damage.
One key takeaway is that drugs traditionally used for other types of infections—fungal, viral, or parasitic—might offer new hope for Lyme disease treatment. Additionally, drugs that target non-infectious diseases, such as cancer or macular degeneration, could be repurposed to fight persistent Lyme infections, although more research is needed to determine their safety and efficacy in humans.
The research team, led by Jie Feng, Megan Weitner, Wanliang Shi, Shuo Zhang, David Sullivan, and Ying Zhang, stresses the importance of conducting further in vitro and in vivo studies to test these drug candidates in combination with existing Lyme antibiotics. The ultimate goal is to develop more effective treatments that can completely eradicate the bacteria, preventing the chronic symptoms seen in PTLDS.
Conclusion
This comprehensive study underscores the complexity of treating persistent Borrelia burgdorferi infections. While current Lyme disease treatments are limited in their ability to fully eliminate the bacteria, the identification of new drug candidates from a diverse range of categories—antibiotics, antifungals, antivirals, and drugs for non-infectious conditions—provides new hope for improving treatment outcomes. The future of Lyme disease treatment may lie in combination therapies that incorporate these new findings, offering a more effective approach to tackling this challenging illness.
Acknowledgments
This research was funded in part by the Global Lyme Alliance and NIH grants AI099512 and AI108535. The contributions of the research team—Jie Feng, Megan Weitner, Wanliang Shi, Shuo Zhang, David Sullivan, and Ying Zhang—represent a significant advancement in understanding how to better target persistent infections in Lyme disease.
Here are the precise measured values of all the drugs used in the experiment:
Antibacterial Agents
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Doxycycline (Lyme antibiotic):
- Microscopy: 75% residual viable cells
- SYBR Green I/PI: 67%
- p-value: 0.23360
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Amoxicillin (Lyme antibiotic):
- Microscopy: 76%
- SYBR Green I/PI: 76%
- p-value: 1.00000
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Cefuroxime (Lyme antibiotic):
- Microscopy: 49%
- SYBR Green I/PI: 43%
- p-value: 0.00032
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Daptomycin (Antibiotic):
- Microscopy: 35%
- SYBR Green I/PI: 28%
- p-value: 0.00001
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3-Formyl Rifamycin (Antibacterial):
- Microscopy: 59%
- SYBR Green I/PI: 42%
- p-value: 0.00103
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Carbenicillin (Antibiotic):
- Microscopy: 64%
- SYBR Green I/PI: 46%
- p-value: 0.06453
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Tazobactam (Antibiotic):
- Microscopy: 56%
- SYBR Green I/PI: 54%
- p-value: 0.10052
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Aztreonam (Antibiotic):
- Microscopy: 50%
- SYBR Green I/PI: 55%
- p-value: 0.08105
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Bacitracin (Antibiotic):
- Microscopy: 60%
- SYBR Green I/PI: 47%
- p-value: 0.06536
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Rifamycin SV (Antibiotic):
- Microscopy: 60%
- SYBR Green I/PI: 63%
- p-value: 0.01872
Antifungal Agents
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Fluconazole (Antifungal):
- Microscopy: 45%
- SYBR Green I/PI: 55%
- p-value: 0.10643
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Mepartricin (Antifungal):
- Microscopy: 60%
- SYBR Green I/PI: 43%
- p-value: 0.03214
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Bifonazole (Antifungal):
- Microscopy: 50%
- SYBR Green I/PI: 48%
- p-value: 0.09243
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Oxiconazole Nitrate (Antifungal):
- Microscopy: 62%
- SYBR Green I/PI: 49%
- p-value: 0.04957
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Nystatin (Antifungal):
- Microscopy: 64%
- SYBR Green I/PI: 64%
- p-value: 0.03312
Antiviral Agents
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Zanamivir (Antiviral):
- Microscopy: 60%
- SYBR Green I/PI: 49%
- p-value: 0.01224
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Nevirapine (Antiviral):
- Microscopy: 51%
- SYBR Green I/PI: 51%
- p-value: 0.01604
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Lamivudine (Antiviral):
- Microscopy: 58%
- SYBR Green I/PI: 58%
- p-value: 0.01121
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Penciclovir (Antiviral):
- Microscopy: 60%
- SYBR Green I/PI: 64%
- p-value: 0.09707
Antimalarial Agents
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Artemesinin (Antimalarial):
- Microscopy: 45%
- SYBR Green I/PI: 49%
- p-value: 0.10432
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Methylene Blue Hydrate (Antimethemoglobinemic):
- Microscopy: 40%
- SYBR Green I/PI: Over range
- p-value: N/A
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Quinaldine Blue (Antimalarial):
- Microscopy: 35%
- SYBR Green I/PI: Over range
- p-value: N/A
Anthelmintic and Antiparasitic Agents
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Tartar Emetic (Anthelmintic):
- Microscopy: 45%
- SYBR Green I/PI: 42%
- p-value: 0.00250
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Toltrazuril (Antiprotozoal):
- Microscopy: 60%
- SYBR Green I/PI: 43%
- p-value: 0.00296
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Oxantel (Anthelmintic):
- Microscopy: 63%
- SYBR Green I/PI: 44%
- p-value: 0.01599
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Pyrimethamine (Antiprotozoal):
- Microscopy: 55%
- SYBR Green I/PI: 45%
- p-value: 0.00030
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Oxfendazole (Anthelmintic):
- Microscopy: 54%
- SYBR Green I/PI: 54%
- p-value: 0.00095
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Flubendazole (Anthelmintic):
- Microscopy: 54%
- SYBR Green I/PI: 54%
- p-value: 0.01183
Non-Infectious Disease Treatments with Activity Against Persisters
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Verteporfin (Ophthalmic):
- Microscopy: 47%
- SYBR Green I/PI: 27%
- p-value: 0.00284
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Pidolic Acid (Antiseptic):
- Microscopy: 45%
- SYBR Green I/PI: 45%
- p-value: 0.00477
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Dextrorphan Tartrate (Analgesic):
- Microscopy: 43%
- SYBR Green I/PI: 47%
- p-value: 0.00361
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Indatraline (Antidepressant):
- Microscopy: 43%
- SYBR Green I/PI: 51%
- p-value: 0.02578
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Oltipraz (Antitumor):
- Microscopy: 55%
- SYBR Green I/PI: 46%
- p-value: 0.00121
Drugs with Limited Clinical Use
- Thonzonium Bromide: A cationic detergent and surfactant that exhibited high activity against stationary phase B. burgdorferi, with similar effectiveness to daptomycin. However, due to its general cellular toxicity in humans, it is not suitable for treating Lyme disease internally.
- Benzododecinium Chloride: Another detergent with strong anti-persister activity. Like thonzonium bromide, it is not suitable for internal use but highlights cell membrane disruption as a potential target for future drugs.