EVALUATION OF DRUG COMBINATIONS AGAINST STATIONARY PHASE AND PERSISTENT BORRELIA IN VITRO
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Lyme disease is the most commonly reported vector-borne disease in the United States. Although most patients respond well to antibiotic treatment, 10-20% suffer chronic symptoms of carditis, arthritis, and neurological impairment months after treatment. The cause of these symptoms is still undetermined, but there are many theories to explain this phenomena including autoimmune activation, the presence of antigenic debris, and treatment-resistant persistent bacteria. Evidence of treatment-resistant and non-culturable Borrelia has been seen in animals, but these results remain controversial. Orally available, low toxicity drugs were tested in combination against Borrelia burgdorferi in vitro to determine if combined use would increase their activity. These combinations were tested against both stationary phase and persistent bacteria using a SYBR Green I/PI rapid viability assay, and were confirmed via epifluorescent microscopy. Several trends were seen among high activity combinations. Triple drug combinations including cefuroxime, a protein synthesis inhibitor [doxycycline, azithromycin, nitrofurantoin, etc.], and a free radical producing drug [methylene blue, artemisinin, etc.] had the highest activity against stationary phase cultures. However, drug combinations targeting DNA transcription [rifabutin] and either membrane permeability or homeostasis mechanisms [fluconazole, hydroxychloroquine, etc.] were highly effective against amoxicillin-treated persisters. These results suggest these pathways may be key targets for future Borrelia treatments.