SQ109: A New Drug Lead for Chagas Disease.
Antimicrob Agents Chemother. 2015 Jan 12;
Authors: Veiga-Santos P, Li K, Lameira L, de Carvalho TM, Huang G, Galizzi M, Shang N, Li Q, Gonzalez-Pacanowska D, Hernandez-Rodriguez V, Benaim G, Guo RT, Urbina JA, Docampo R, de Souza W, Oldfield E
We tested the anti-tuberculosis drug SQ109, currently in advanced clinical trials for the treatment of drug-susceptible and drug-resistant tuberculosis, for its in vitro activity against the trypanosomatid parasite Trypanosoma cruzi, the causative agent of Chagas disease. SQ109 was a potent inhibitor of the trypomastigote form of the parasite with an IC50 for cell killing of 50 ± 8 nM but had little effect (EC50∼80 μM) in a red blood cell hemolysis assay. It also inhibited extracellular epimastigotes (IC50 = 4.6 ± 1 μM) and the clinically relevant, intracellular amastigotes (IC50∼0.5-1 μM) with a selectivity index of ∼10-20. SQ109 caused major ultra-structural changes in all three life-cycle forms, as observed by light microscopy, SEM and TEM. It rapidly collapsed the inner mitochondrial membrane potential (Δψm) in succinate-energized mitochondria, acting in the same manner as the uncoupler FCCP, and caused alkalinization of internal acidic compartments, effects that are likely to make major contributions to its mechanism of action. The compound also had activity against squalene synthase, binding to its active site; it inhibited sterol side-chain reduction and, in the amastigote assay, acted synergistically with the anti-fungal drug posaconazole with a fractional inhibitory concentration index (FICI) of 0.48, but these effects are unlikely to account for the rapid effects seen on cell morphology and cell killing. SQ109 thus most likely acts, at least in part, by collapsing Δψ/ΔpH, one of the major mechanisms demonstrated previously for its action against Mycobacterium tuberculosis. Overall, the results suggest that SQ109, currently in advanced clinical trials for the treatment of drug-susceptible and drug-resistant tuberculosis, may also have potential as a drug lead against Chagas disease.
PMID: 25583723 [PubMed - as supplied by publisher]