Repurposing disulfiram (Tetraethylthiuram Disulfide) as a potential drug candidate against Borrelia burgdorferi in vitro and in vivo

Potula, H.-H. s.; Shahryari, J.; Inayathullah, M.; Malkovskiy, A. V.; Kim, K.-M.; Rajadas, J.

doi:10.1101/842286

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bioRxiv · 10.1101/842286

Repurposing disulfiram (Tetraethylthiuram Disulfide) as a potential drug candidate against Borrelia burgdorferi in vitro and in vivo

Potula, H.-H. s.·Shahryari, J.·Inayathullah, M.·Malkovskiy, A. V.·Kim, K.-M.·Rajadas, J.

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Abstract

Lyme disease caused by the Borrelia burgdorferi (Bb or B. burgdorferi) is a most common vector-borne, multi-systemic disease in USA. Although, most Lyme disease patients can be cured with a course of antibiotic treatment, a significant percent of patient population fail to be disease-free post-treatment, necessitating the development of more effective therapeutics. We previously found several drugs including disulfiram having with good activity against B. burgdorferi. In current study, we evaluated the potential of repurposing the FDA approved disulfiram drug for its borreliacidal activity. Our in vitro results indicate disulfiram shows excellent borreliacidal activity against both the log and stationary phase B. burgdorferi. Subsequent mice studies have determined that the disulfiram eliminated B. burgdorferi completely from hearts and urinary bladder by day 28 post infection, demonstrating the practical application and efficacy of disulfiram against B. burgdorferi in vivo. Moreover, disulfiram treated mice showed reduced expression of inflammatory markers and protected against histopathology and organ damage. Furthermore, disulfiram treated mice showed significantly lower amounts of total antibody titers (IgM and IgG) at day 21 and total IgG2b at day 28 post infection. Mechanistically, cellular analysis of lymph nodes revealed a decrease in percentage of CD19+ B cells and increase in total percentage of CD3+ T cells, CD3+ CD4+ T helpers, and naive and effector memory cells in disulfiram-treated mice. Together, we demonstrate that disulfiram has the potential and could be repurposed as an effective antibiotic for treating Lyme disease in near future.

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Potula, H.-H. s., Shahryari, J., Inayathullah, M., Malkovskiy, A. V., Kim, K.-M., Rajadas, J.. 2019-11-15. Repurposing disulfiram (Tetraethylthiuram Disulfide) as a potential drug candidate against Borrelia burgdorferi in vitro and in vivo. https://doi.org/10.1101/842286

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