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Exploring New Treatments for Lyme Disease: A Study on Drug Candidates Targeting Persistent Borrelia

New Drug Discoveries for Treating Persistent Lyme Disease Infections

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New Drug Discoveries for Treating Persistent Lyme Disease Infections
Explore breakthrough drugs targeting persistent Lyme disease infections that standard antibiotics can't treat, offering new hope for Post-Treatment Lyme Syndrome.

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:

  • 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.

  • 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.

  • 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.

  • 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.

  • 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

  • Doxycycline (Lyme antibiotic):

    • Microscopy: 75% residual viable cells
    • SYBR Green I/PI: 67%
    • p-value: 0.23360
  • Amoxicillin (Lyme antibiotic):

    • Microscopy: 76%
    • SYBR Green I/PI: 76%
    • p-value: 1.00000
  • Cefuroxime (Lyme antibiotic):

    • Microscopy: 49%
    • SYBR Green I/PI: 43%
    • p-value: 0.00032
  • Daptomycin (Antibiotic):

    • Microscopy: 35%
    • SYBR Green I/PI: 28%
    • p-value: 0.00001
  • 3-Formyl Rifamycin (Antibacterial):

    • Microscopy: 59%
    • SYBR Green I/PI: 42%
    • p-value: 0.00103
  • Carbenicillin (Antibiotic):

    • Microscopy: 64%
    • SYBR Green I/PI: 46%
    • p-value: 0.06453
  • Tazobactam (Antibiotic):

    • Microscopy: 56%
    • SYBR Green I/PI: 54%
    • p-value: 0.10052
  • Aztreonam (Antibiotic):

    • Microscopy: 50%
    • SYBR Green I/PI: 55%
    • p-value: 0.08105
  • Bacitracin (Antibiotic):

    • Microscopy: 60%
    • SYBR Green I/PI: 47%
    • p-value: 0.06536
  • Rifamycin SV (Antibiotic):

    • Microscopy: 60%
    • SYBR Green I/PI: 63%
    • p-value: 0.01872

Antifungal Agents

  • Fluconazole (Antifungal):

    • Microscopy: 45%
    • SYBR Green I/PI: 55%
    • p-value: 0.10643
  • Mepartricin (Antifungal):

    • Microscopy: 60%
    • SYBR Green I/PI: 43%
    • p-value: 0.03214
  • Bifonazole (Antifungal):

    • Microscopy: 50%
    • SYBR Green I/PI: 48%
    • p-value: 0.09243
  • Oxiconazole Nitrate (Antifungal):

    • Microscopy: 62%
    • SYBR Green I/PI: 49%
    • p-value: 0.04957
  • Nystatin (Antifungal):

    • Microscopy: 64%
    • SYBR Green I/PI: 64%
    • p-value: 0.03312

Antiviral Agents

  • Zanamivir (Antiviral):

    • Microscopy: 60%
    • SYBR Green I/PI: 49%
    • p-value: 0.01224
  • Nevirapine (Antiviral):

    • Microscopy: 51%
    • SYBR Green I/PI: 51%
    • p-value: 0.01604
  • Lamivudine (Antiviral):

    • Microscopy: 58%
    • SYBR Green I/PI: 58%
    • p-value: 0.01121
  • Penciclovir (Antiviral):

    • Microscopy: 60%
    • SYBR Green I/PI: 64%
    • p-value: 0.09707

Antimalarial Agents

  • Artemesinin (Antimalarial):

    • Microscopy: 45%
    • SYBR Green I/PI: 49%
    • p-value: 0.10432
  • Methylene Blue Hydrate (Antimethemoglobinemic):

    • Microscopy: 40%
    • SYBR Green I/PI: Over range
    • p-value: N/A
  • Quinaldine Blue (Antimalarial):

    • Microscopy: 35%
    • SYBR Green I/PI: Over range
    • p-value: N/A

Anthelmintic and Antiparasitic Agents

  • Tartar Emetic (Anthelmintic):

    • Microscopy: 45%
    • SYBR Green I/PI: 42%
    • p-value: 0.00250
  • Toltrazuril (Antiprotozoal):

    • Microscopy: 60%
    • SYBR Green I/PI: 43%
    • p-value: 0.00296
  • Oxantel (Anthelmintic):

    • Microscopy: 63%
    • SYBR Green I/PI: 44%
    • p-value: 0.01599
  • Pyrimethamine (Antiprotozoal):

    • Microscopy: 55%
    • SYBR Green I/PI: 45%
    • p-value: 0.00030
  • Oxfendazole (Anthelmintic):

    • Microscopy: 54%
    • SYBR Green I/PI: 54%
    • p-value: 0.00095
  • Flubendazole (Anthelmintic):

    • Microscopy: 54%
    • SYBR Green I/PI: 54%
    • p-value: 0.01183

Non-Infectious Disease Treatments with Activity Against Persisters

  • Verteporfin (Ophthalmic):

    • Microscopy: 47%
    • SYBR Green I/PI: 27%
    • p-value: 0.00284
  • Pidolic Acid (Antiseptic):

    • Microscopy: 45%
    • SYBR Green I/PI: 45%
    • p-value: 0.00477
  • Dextrorphan Tartrate (Analgesic):

    • Microscopy: 43%
    • SYBR Green I/PI: 47%
    • p-value: 0.00361
  • Indatraline (Antidepressant):

    • Microscopy: 43%
    • SYBR Green I/PI: 51%
    • p-value: 0.02578
  • 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.

Ongoing Research & Discussion on “Exploring New Treatments for Lyme Disease: A Study on Drug Candidates Targeting Persistent Borrelia”

Review and Analysis: Advances in Drug Discovery for Persistent Lyme Disease

Lyme disease, caused by the bacterium Borrelia burgdorferi, remains a significant public health concern, particularly due to the challenges associated with persistent infections that evade conventional treatment. Despite the availability of antibiotics like doxycycline and amoxicillin, a substantial percentage of patients—estimated between 10-20%—continue to suffer from chronic symptoms even after completing their prescribed treatment course. This phenomenon is referred to as Post-Treatment Lyme Disease Syndrome (PTLDS), and it has sparked intense debate within the scientific and medical communities. Recent advances in drug discovery, as explored in the study led by Jie Feng, Megan Weitner, Wanliang Shi, Shuo Zhang, David Sullivan, and Ying Zhang, provide a promising outlook for the future of Lyme disease treatment, particularly by targeting the so-called persisters—dormant forms of Borrelia burgdorferi that evade destruction by traditional antibiotics.

The Limitations of Conventional Antibiotics in Lyme Disease Treatment

One of the most compelling aspects of this research is its acknowledgment of the shortcomings of current Lyme disease treatment protocols. Antibiotics like doxycycline and amoxicillin, while effective in eliminating actively growing bacteria, are significantly less effective against stationary phase persisters. These dormant bacterial cells are metabolically inactive, making them resistant to drugs that target processes like cell wall synthesis, protein production, or DNA replication. As a result, persisters survive the initial antibiotic treatment, allowing the infection to persist and leading to the debilitating symptoms of PTLDS.

This study sheds light on an important, yet underexplored, aspect of Lyme disease: the role of bacterial morphology and behavior in treatment resistance. The authors provide evidence that B. burgdorferi changes its form and reduces its metabolic activity in response to environmental stressors such as antibiotics. These changes allow the bacteria to "hide" from the immune system and drugs, continuing to cause damage long after the initial infection.

Drug Discovery: A Step Forward in Targeting Persisters

The strength of this study lies in its comprehensive screening of an FDA-approved drug library to identify compounds that show activity against Borrelia persisters. The authors screened 113 drug hits that showed higher activity against stationary-phase B. burgdorferi than traditional Lyme antibiotics. The range of drugs identified in the study is striking, and the diversity of the drug classes adds weight to the argument that a multi-pronged approach to Lyme treatment may be the key to overcoming persisters.

Notably, the study identified drugs that are not traditionally used to treat bacterial infections but still exhibited significant efficacy against B. burgdorferi persisters. For instance, verteporfin, a drug used to treat macular degeneration, showed substantial activity in killing dormant bacteria. Verteporfin works by generating reactive oxygen species (ROS) that disrupt cell membranes and damage bacterial cells. This discovery is particularly interesting because it highlights the potential of repurposing drugs used for non-infectious diseases to target persistent bacterial infections. It also points to the importance of oxidative stress as a mechanism for killing persisters.

In addition to verteporfin, several antifungal and antiviral drugs showed promising results. For example, fluconazole, an antifungal commonly used to treat yeast infections, was effective in killing a significant portion of Borrelia persisters. Similarly, the antiviral zanamivir also showed activity against persisters, which raises questions about the potential shared vulnerabilities between persister bacteria and other pathogens like fungi and viruses. These findings suggest that broad-spectrum antimicrobials, or drugs that work via mechanisms unrelated to bacterial growth inhibition, may be more effective in treating persistent infections.

The Importance of Membrane-Disrupting Agents

One of the key takeaways from this study is the potential role of membrane-disrupting agents in targeting Borrelia persisters. Several of the drugs identified in the study, including daptomycin, benzododecinium chloride, and thonzonium bromide, act by disrupting bacterial cell membranes. Membrane-disrupting agents may have a unique advantage in treating persistent infections because they can damage bacterial cells regardless of their metabolic state.

This is significant because persisters, being metabolically inactive, are inherently resistant to drugs that target active cellular processes. By disrupting the bacterial membrane, these drugs can effectively "kill" persisters without relying on the bacteria being in an active, replicating state. The success of daptomycin, which is already used clinically to treat complicated bacterial infections, offers a potential avenue for the development of similar drugs that specifically target persistent Lyme disease infections.

Mechanisms of Resistance and Future Directions

While the findings of this study are promising, they also raise important questions about the mechanisms of resistance in Borrelia burgdorferi persisters. The authors suggest that efflux pumps—proteins that bacteria use to pump out toxic substances, including antibiotics—may play a role in the persistence of Borrelia after antibiotic treatment. This hypothesis is supported by the observation that drugs known to inhibit bacterial efflux pumps could be lead compounds for the development of more effective treatments for PTLDS.

The study also underscores the need for combination therapies. Since no single drug was able to completely eradicate the persisters, a combination of drugs that target different bacterial processes—such as membrane disruption, energy production inhibition, and ROS generation—may be the most effective strategy for treating persistent infections. Future research should focus on identifying the most effective drug combinations and testing them in both in vitro and in vivo models to validate their potential clinical use.

Clinical Relevance and Challenges

While this study provides a wealth of information about potential treatments for persistent Lyme disease infections, there are several challenges that must be addressed before these findings can be translated into clinical practice. One major limitation is that the experiments were conducted in a cell-free culture system, which does not account for the complexities of the human body, such as drug absorption, tissue penetration, and immune system interactions.

Furthermore, many of the drugs identified in the study, such as thonzonium bromide and benzododecinium chloride, are not suitable for internal use due to their toxicity. These findings highlight the need for continued research into safe, effective drug combinations that can be used in human patients. Additionally, the study's reliance on an SYBR Green I/PI assay and other culture-based viability assays, while useful for identifying promising drug candidates, does not fully capture the intricacies of persistent infections in a living host.

Another challenge is the political and medical debate surrounding PTLDS and the recognition of persistent Borrelia infections. Despite mounting evidence of persistence, the condition is still not universally accepted as an ongoing infection, and treatment options remain limited. This study, however, adds important data to the growing body of research advocating for the need to better understand and treat persistent infections in Lyme disease patients.

Conclusion

This study by Jie Feng and colleagues represents a significant step forward in our understanding of how to target persistent Borrelia burgdorferi infections. By identifying drugs that show greater activity against persisters than conventional antibiotics, the researchers have opened the door to new treatment possibilities for patients suffering from PTLDS. The identification of non-antibiotic drugs with strong anti-persister activity, the focus on membrane-disrupting agents, and the potential for repurposing drugs from other fields all represent promising avenues for future research.

However, significant challenges remain, particularly in translating these findings into safe, effective treatments for human patients. As the debate over PTLDS continues, studies like this one will play a crucial role in advancing our understanding of persistent infections and developing better treatment strategies for Lyme disease patients.

References

  1. Identification of Additional Anti-Persister Activity against Borrelia burgdorferi from an FDA Drug Library
    Author: Jie Feng et al.
    Publisher: MDPI
    URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4790293/

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