Repurposing Disulfiram (Tetraethylthiuram Disulfide) as a Potential Drug Candidate against Borrelia burgdorferi In Vitro and In Vivo.

Hari-Hara S K Potula,Kwang-Min Kim,Mohammed Inayathullah,Jayakumar Rajadas,Andrey Victorovich Malkovskiy,Jahanbanoo Shahryari

doi:10.3390/antibiotics9090633

Hari-Hara S K Potula, Kwang-Min Kim + Show 4 more

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https://doi.org/10.3390/antibiotics9090633

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Abstract

Lyme disease caused by the Borrelia burgdorferi (Bb or B. burgdorferi) is the most common vector-borne, multi-systemic disease in the USA. Although most Lyme disease patients can be cured with a course of the first line of antibiotic treatment, some patients are intolerant to currently available antibiotics, necessitating the development of more effective therapeutics. We previously found several drugs, including disulfiram, that exhibited effective activity against B. burgdorferi. In the current study, we evaluated the potential of repurposing the FDA-approved drug, disulfiram for its borreliacidal activity. Our results indicate disulfiram has excellent borreliacidal activity against both the log and stationary phase B. burgdorferi sensu stricto B31 MI. Treatment of mice with disulfiram eliminated the B. burgdorferi sensu stricto B31 MI completely from the hearts and urinary bladder by day 28 post infection. Moreover, disulfiram-treated mice showed reduced expressions of inflammatory markers, and thus they were protected from histopathology and cardiac 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. FACS analysis of lymph nodes revealed a decrease in the percentage of CD19+ B cells and an increase in total percentage of CD3+ T cells, CD3+ CD4+ T helpers, and naive and effector memory cells in disulfiram-treated mice. Together, our findings suggest that disulfiram has the potential to be repurposed as an effective antibiotic for treating Lyme disease.

Highlights

Lyme disease, a Zoonosis, is the most commonly reported vector-borne disease in the UnitedStates and approximately affects 300,000 individuals annually in North America [1] and is spread by the spirochete Borrelia burgdorferi sensu stricto
We evaluated the antibacterial activities of disulfiram against log- and stationary phase cultures of B. burgdorferi sensu stricto B31 MI
Whereas our initial screen of disulfiram from four drug libraries is based on Bac titer-Glo assay [15], we followed up on these studies and performed our preliminary assays using varying concentrations of disulfiram ranging from 100 μM to 0.625 μM by Bac titer-Glo assay, which measures the cell viability based on quantitation of ATP present, but it cannot discriminate between the inhibitory or bactericidal effects of the disulfiram

Summary

Introduction

A Zoonosis, is the most commonly reported vector-borne disease in the UnitedStates and approximately affects 300,000 individuals annually in North America [1] and is spread by the spirochete Borrelia burgdorferi sensu stricto (hereafter termed B. burgdorferi or Bb). A Zoonosis, is the most commonly reported vector-borne disease in the United. The clinical manifestations of Lyme disease include three phases [2]. Infection involves localized erythema migrans, followed within days or weeks by dissemination to the nervous system, heart, or joints. 60% of patients with Lyme disease in the United States develop arthritis, which may recur at intervals and last for months or years. A fewer number of patients (4 to 10%) suffer carditis, which is an early and nonrecurring manifestation of the infection [3]. The antibiotic treatment using oral doxycycline is effective for most patients at the early localized stage of Lyme disease [4]

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