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Título : SQ109, a New Drug Lead for Chagas Disease
Autor : Veiga-Santos, Phercyles
Li, Kai
Lameira, Lilianne
Ulisses de Carvalho, Tecia Maria
Huang, Guozhong
Galizzi, Melina
Shang, Na
Li, Qian
Gonzalez-Pacanowska, Dolores
Hernandez-Rodriguez, Vanessa
Benaím, Gustavo
Guo, Rey-Ting
Urbina, Julio A.
Docampo, Roberto
de Souza, Wanderley
Oldfield, Eric
Palabras clave : antituberculosis
drug SQ109
trypanosomatid parasite
Chagas disease
cell killing
Fecha de publicación : 2015
Editorial : Antimicrobial Agents and Chemotherapy
Citación : Vol. 59;No. 4 pp. 1950-1961
Resumen : We tested the antituberculosis drug SQ109, which is 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 found to be a potent inhibitor of the trypomastigote form of the parasite, with a 50% inhibitory concentration (IC50) for cell killing of 50±8 nM, but it had little effect (50% effective concentration [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 to 1 µM), with a selectivity index of~10 to 20. SQ109 caused major ultrastructural changes in all three life cycle forms, as observed by light microscopy, scanning electron microscopy (SEM), and transmission electron microscopy (TEM). It rapidly collapsed the inner mitochondrial membrane potential (∆Ψm) in succinate-energized mitochondria, acting in the same manner as the uncoupler FCCP [carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone], and it caused the 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 antifungal 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 ∆Ψ/∆pH, one of the major mechanisms demonstrated previously for its action against Mycobacterium tuberculosis. Overall, the results suggest that SQ109, which is 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.
ISSN : 1098-6596 (Electronic)
0066-4804 (Linking)
0066-4804 (Print)
doi: 10.1128/AAC.03972-14.
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