Abstract
Lyme disease is a leading vector-borne disease in the United States. Although the majority of Lyme patients can be cured with standard 2–4 week antibiotic treatment, 10%–20% of patients continue to suffer from prolonged post-treatment Lyme disease syndrome (PTLDS). While the cause for this is unclear, persisting organisms not killed by current Lyme antibiotics may be involved. In our previous study, we screened an FDA drug library and reported 27 top hits that showed high activity against Borrelia persisters. In this study, we present the results of an additional 113 active hits that have higher activity against the stationary phase B. burgdorferi than the currently used Lyme antibiotics. Many antimicrobial agents (antibiotics, antivirals, antifungals, anthelmintics or antiparasitics) used for treating other infections were found to have better activity than the current Lyme antibiotics. These include antibacterials such as rifamycins (3-formal-rifamycin, rifaximin, rifamycin SV), thiostrepton, quinolone drugs (sarafloxacin, clinafloxacin, tosufloxacin), and cell wall inhibitors carbenicillin, tazobactam, aztreonam; antifungal agents such as fluconazole, mepartricin, bifonazole, climbazole, oxiconazole, nystatin; antiviral agents zanamivir, nevirapine, tilorone; antimalarial agents artemisinin, methylene blue, and quidaldine blue; antihelmintic and antiparasitic agents toltrazuril, tartar emetic, potassium antimonyl tartrate trihydrate, oxantel, closantel, hycanthone, pyrimethamine, and tetramisole. Interestingly, drugs used for treating other non-infectious conditions including verteporfin, oltipraz, pyroglutamic acid, pidolic acid, and dextrorphan tartrate, that act on the glutathione/γ-glutamyl pathway involved in protection against free radical damage, and also the antidepressant drug indatraline, were found to have high activity against stationary phase B. burgdorferi. Among the active hits, agents that affect cell membranes, energy production, and reactive oxygen species production are more active against the B. burgdorferi persisters than the commonly used antibiotics that inhibit macromolecule biosynthesis. Future studies are needed to evaluate and optimize the promising active hits in drug combination studies in vitro and also in vivo in animal models. These studies may have implications for developing more effective treatments of Lyme disease.
Highlights
Borrelia burgdorferi is the causative agent of Lyme disease, the most common vector-borne disease in the United States and Europe
We identified 165 hits with higher activity against B. burgdorferi persisters than the currently used Lyme antibiotics
It is interesting to note that several highly active drugs identified in our screen, including verteporfin, oltipraz, pyroglutamic acid, pidolic acid (Figure 1), and dextrorphan tartrate, act on the glutathione/γ-glutamyl pathway used in mammalian cells which involved in protection against intracellular damage from free radicals and peroxides
Summary
Borrelia burgdorferi is the causative agent of Lyme disease, the most common vector-borne disease in the United States and Europe. According to the CDC, about 10%–20% of patients receiving this treatment experience chronic symptoms such as fatigue, muscle pain, and neurological impairment even six months after treatment [5], but a more recent study estimated the percentage of such patients to be at least 20% [6]. Patients with these symptoms are diagnosed with Post-Treatment Lyme. Administration (FDA) drug library and identified 165 hits with higher activity against B. burgdorferi persisters than the currently used Lyme antibiotics amoxicillin and doxycycline [18]. We present findings on the remainder of the 113 drug candidates from the FDA drug library with higher activity against the B. burgdorferi stationary phase culture than amoxicillin and doxycycline
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