title: SQ109, a new drug lead for Chagas disease.
abstract: 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 (Δψm) 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 Δψ/ΔpH, 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.
authors.affiliation: Laboratório de Ultraestrutura Celular Hertha Meyer, CCS, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Bloco G, Ilha do Fundão, Rio de Janeiro, Brazil Instituto Nacional de Ciência e Tecnologia em Biologia Estrutural e Bioimagens, Universidade Federal do Rio de Janeiro, Cidade Universitária, Ilha do Fundão, Rio de Janeiro, Brazil.
authors.forename: Phercyles
authors.initials: P
authors.lastname: Veiga-Santos
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.
authors.forename: Kai
authors.initials: K
authors.lastname: Li
authors.affiliation: Laboratório de Ultraestrutura Celular Hertha Meyer, CCS, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Bloco G, Ilha do Fundão, Rio de Janeiro, Brazil.
authors.forename: Lilianne
authors.initials: L
authors.lastname: Lameira
authors.affiliation: Laboratório de Ultraestrutura Celular Hertha Meyer, CCS, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Bloco G, Ilha do Fundão, Rio de Janeiro, Brazil Instituto Nacional de Ciência e Tecnologia em Biologia Estrutural e Bioimagens, Universidade Federal do Rio de Janeiro, Cidade Universitária, Ilha do Fundão, Rio de Janeiro, Brazil.
authors.forename: Tecia Maria Ulisses
authors.initials: TM
authors.lastname: de Carvalho
authors.affiliation: Center for Tropical and Emerging Global Diseases and Department of Cellular Biology, University of Georgia, Athens, Georgia, USA.
authors.forename: Guozhong
authors.initials: G
authors.lastname: Huang
authors.affiliation: Center for Tropical and Emerging Global Diseases and Department of Cellular Biology, University of Georgia, Athens, Georgia, USA.
authors.forename: Melina
authors.initials: M
authors.lastname: Galizzi
authors.affiliation: Industrial Enzymes National Engineering Laboratory, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin, China.
authors.forename: Na
authors.initials: N
authors.lastname: Shang
authors.affiliation: Industrial Enzymes National Engineering Laboratory, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Li
authors.affiliation: Instituto de Parasitología y Biomedicina López-Neyra, Consejo Superior de Investigaciones Cientificas, Granada, Spain.
authors.forename: Dolores
authors.initials: D
authors.lastname: Gonzalez-Pacanowska
authors.affiliation: Laboratorio de Señalización Celular y Bioquímica de Parásitos, Instituto de Estudios Avanzados (IDEA), Caracas, Venezuela.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Hernandez-Rodriguez
authors.affiliation: Laboratorio de Señalización Celular y Bioquímica de Parásitos, Instituto de Estudios Avanzados (IDEA), Caracas, Venezuela.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Benaim
authors.affiliation: Industrial Enzymes National Engineering Laboratory, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin, China.
authors.forename: Rey-Ting
authors.initials: RT
authors.lastname: Guo
authors.affiliation: Instituto Venezolano de Investigaciones Cientificas, Caracas, Venezuela.
authors.forename: Julio A
authors.initials: JA
authors.lastname: Urbina
authors.affiliation: Center for Tropical and Emerging Global Diseases and Department of Cellular Biology, University of Georgia, Athens, Georgia, USA.
authors.forename: Roberto
authors.initials: R
authors.lastname: Docampo
authors.affiliation: Laboratório de Ultraestrutura Celular Hertha Meyer, CCS, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Bloco G, Ilha do Fundão, Rio de Janeiro, Brazil Instituto Nacional de Ciência e Tecnologia em Biologia Estrutural e Bioimagens, Universidade Federal do Rio de Janeiro, Cidade Universitária, Ilha do Fundão, Rio de Janeiro, Brazil Instituto Nacional de Metrologia, Qualidade e Tecnologia (Inmetro), Duque de Caxias, Rio de Janeiro, Brazil.
authors.forename: Wanderley
authors.initials: W
authors.lastname: de Souza
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA eoldfiel@illinois.edu.
authors.forename: Eric
authors.initials: E
authors.lastname: Oldfield
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000818:Animals; D014355:Chagas Disease / Q000188:drug therapy*; D005029:Ethylenediamines / Q000627:therapeutic use*; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D018374:LLC-PK1 Cells; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D013185:Squalene / Q000037:antagonists & inhibitors; D013261:Sterols / Q000096:biosynthesis; D013552:Swine; D014230:Triazoles / Q000494:pharmacology; D014344:Trypanocidal Agents / Q000627:therapeutic use*; D014349:Trypanosoma cruzi / Q000187:drug effects
chemical_list: D005029:Ethylenediamines; C506841:N-geranyl-N'-(2-adamantyl)ethane-1,2-diamine; D013261:Sterols; D014230:Triazoles; D014344:Trypanocidal Agents; C101425:posaconazole; D013185:Squalene; D000218:Adamantane