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

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.

“Repurposing” Disulfiram in the Treatment of Lyme Disease and Babesiosis: Retrospective Review of First 3 Years’ Experience in One Medical Practice

“…In vitro, Alvarez-Manzo et al [29] found disulfiram to be less effective than drugs like clarithromycin and nitroxoline at 5 µg/mL (16.9 µM), while Pothineni et al found disulfiram be extremely effective at its minimum bactericidal concentration of 1.25 µM (0.371 µg/mL) [17], and Potula et al found disulfiram to decrease in efficacy in concentrations greater than 5 µM (1.48 µg/mL). Together, these conclusions suggest that disulfiram becomes less effective at higher concentrations, which is supported by the fact that colloidal forms of disulfiram arise at higher concentrations [22]. Potula et al also provide evidence from in vivo murine experiments that disulfiram was able to clear B. burgdorferi in 28 days post-infection, suppress cardiac inflammatory responses, and reduce the amount of antibody produced [22].…”

“…Together, these conclusions suggest that disulfiram becomes less effective at higher concentrations, which is supported by the fact that colloidal forms of disulfiram arise at higher concentrations [22]. Potula et al also provide evidence from in vivo murine experiments that disulfiram was able to clear B. burgdorferi in 28 days post-infection, suppress cardiac inflammatory responses, and reduce the amount of antibody produced [22].…”

“…As for the mechanism by which disulfiram inhibits B. burgdorferi, it is known that disulfiram is an electrophile that is able to form disulfides with other thiol-bearing molecules [22]. B. burgdorferi has a variety of cofactors [23] containing thiophilic residues, which can be disrupted by disulfiram through thiol-disulfide exchanges.…”

A Bilayer Vaginal Tablet for the Localized Delivery of Disulfiram and 5-Fluorouracil to the Cervix

“…Therefore, to reduce the amount of 5-FU required, a co-drug was incorporated to produce a synergistic effect and increase safety and the efficacy of the formulation [19]. One approach to expedite the development of novel formulations is to repurpose pre-existing drugs that have been approved for the treatment of other medical conditions [20]. Disulfiram (DSF), a drug currently used in the treatment of chronic alcoholism, has been shown to possess anti-tumor activity [21].…”

Why disulfiram is not a panacea?

“…Judging according to published scientific literature, disulfiram seems to be promising treatment for conditions as distinct as Alzheimer's disease (Reinhardt et al, 2018), obesity (Bernier et al, 2020, tuberculosis (Dalecki et al 2015), lyme borreliosis (Potula et al, 2020), and even for current pandemic. Indeed, two recent studies in Nature and Nature Immunology suggest that disulfiram could treat covid-19 (Jin et al, 2020) and sepsis (Hu et al, 2020), respectively.…”