Abstract
SQ109 is an anti-tubercular drug candidate that has completed Phase IIb/III clinical trials for tuberculosis and has also been shown to exhibit potent in vitro efficacy against protozoan parasites including Leishmania and Trypanosoma cruzi spp. However, its in vivo efficacy against protozoa has not been reported. Here, we evaluated the activity of SQ109 in mouse models of Leishmania, Trypanosoma spp. as well as Toxoplasma infection. In the T. cruzi mouse model, 80% of SQ109-treated mice survived at 40 days post-infection. Even though SQ109 did not cure all mice, these results are of interest since they provide a basis for future testing of combination therapies with the azole posaconazole, which acts synergistically with SQ109 in vitro. We also found that SQ109 inhibited the growth of Toxoplasma gondii in vitro with an IC50 of 1.82 µM and there was an 80% survival in mice treated with SQ109, whereas all untreated animals died 10 days post-infection. Results with Trypanosoma brucei and Leishmania donovani infected mice were not promising with only moderate efficacy. Since SQ109 is known to be extensively metabolized in animals, we investigated the activity in vitro of SQ109 metabolites. Among 16 metabolites, six mono-oxygenated forms were found active across the tested protozoan parasites, and there was a ~6× average decrease in activity of the metabolites as compared to SQ109 which is smaller than the ~25× found with mycobacteria.
Highlights
For T. cruzi, the activity of SQ109 was assessed for trypomastigotes, epimastigotes, and intracellular amastigotes, with benznidazole as a control
As part of a drug repurposing strategy for kinetoplastid diseases, the activity of SQ109 has been evaluated against T. brucei, T. cruzi and Leishmania species in vitro by several research groups, and potent activity was reported against all three parasites [8–11]
There have been no reports evaluating the anti-parasitic efficacy of SQ109 in any animal models so in this study, we assessed the therapeutic potential of SQ109 in acute mouse models of T. brucei and T. cruzi infections, as well as L
Summary
SQ109 is an anti-tubercular drug candidate that has completed Phase IIb/III clinical trials for tuberculosis and has been shown to exhibit potent in vitro efficacy against protozoan parasites including Leishmania and Trypanosoma cruzi spp. Amphotericin B (Figure 1), used to treat fungal infections, and miltefosine, originally developed as an anti-cancer drug, have been successfully repurposed for treating visceral leishmaniasis (VL) [1,2]. Another example is fexinidazole, very recently approved The anti-antiarrhythmic drug amiodarone has both in vitro and in vivo activity against T. cruzi and acts synergistically with posaconazole, published maps and institutional affiliations
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
