Journal
INTERNATIONAL JOURNAL OF ANTIMICROBIAL AGENTS
Volume 54, Issue 1, Pages 85-88Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ijantimicag.2019.04.002
Keywords
Disulfiram; Francisella tularensis; Drug repurposing; Bioinformatics; MIC
Funding
- UK Ministry of Defence (United Kingdom)
- Instituto Gulbenkian de Ciencia (Oeiras, Portugal)
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Disulfiram (DSF) can help treat alcohol dependency by inhibiting aldehyde dehydrogenase (ALDH). Genomic analysis revealed that Francisella tularensis, the causative agent of tularemia, has lost all but one ALDH-like domain and that this domain retains the target of DSF. In this study, minimum inhibitory concentration (MIC) assays demonstrated that both DSF and its primary metabolite diethyldithiocarbamate (DDC) have strong antimicrobial activity against F. tularensis strain SCHU S4, with the MIC of DSF determined as 2 mu g/mL in comparison with 8 mu g/mL for DDC. The activity of DSF was further confirmed using an in vitro human macrophage infection assay. Francisella tularensis bacteria in DSF-treated cells were reduced in comparison with untreated and DDC-treated cells, comparable with that observed in doxycycline-treated cells. This suggests that DSF may be suitable for further investigation as an in vivo therapy for tularemia. Crown Copyright (C) 2019 Published by Elsevier B.V.
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