Navegar

Colección

Datos Estadísticas

Artículo

Estamos trabajando para incorporar este artículo al repositorio
Consulte el artículo en la página del editor
Consulte la política de Acceso Abierto del editor

Abstract:

Bisphosphonates are widely used for the treatment of bone disorders. These drugs also inhibit the growth of a variety of protozoan parasites, such as Toxoplasma gondii, the etiologic agent of toxoplasmosis. The target of the most potent bisphosphonates is the isoprenoid biosynthesis pathway enzyme farnesyl diphosphate synthase (FPPS). Based on our previous work on the inhibitory effect of sulfur-containing linear bisphosphonates against T. gondii, we investigated the potential synergistic interaction between one of these derivatives, 1-[(n-heptylthio)ethyl]-1,1-bisphosphonate (C7S), and statins, which are potent inhibitors of the host 3-hydroxy-3-methyl glutaryl-coenzyme A reductase (3-HMG-CoA reductase). C7S showed high activity against the T. gondii bifunctional farnesyl diphosphate (FPP)/geranylgeranyl diphosphate (GGPP) synthase (TgFPPS), which catalyzes the formation of FPP and GGPP (50% inhibitory concentration [IC50] = 31 ± 0.01 nM [mean ± standard deviation]), and modest effect against the human FPPS (IC50 = 1.3 ± 0.5 μM). We tested combinations of C7S with statins against the in vitro replication of T. gondii. We also treated mice infected with a lethal dose of T. gondii with similar combinations. We found strong synergistic activities when using low doses of C7S, which were stronger in vivo than when tested in vitro. We also investigated the synergism of several commercially available bisphosphonates with statins both in vitro and in vivo. Our results provide evidence that it is possible to develop drug combinations that act synergistically by inhibiting host and parasite enzymes in vitro and in vivo. © 2017 American Society for Microbiology. All Rights Reserved.

Registro:

Documento: Artículo
Título:Synergistic activity between statins and bisphosphonates against acute experimental toxoplasmosis
Autor:Li, Z.-H.; Li, C.; Szajnman, S.H.; Rodriguez, J.B.; Moreno, S.N.J.
Filiación:Center for Tropical and Emerging Global Diseases, Department of Cellular Biology, University of Georgia, Athens, GA, United States
Departamento de Química Orgánica, UMYMFOR (CONICET-FCEyN), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina
Palabras clave:Bisphosphonate; Isoprenoids; Statins; Synergy; Toxoplasma gondii; 1 [(n heptylthio)ethyl] 1,1 bisphosphonate; alendronic acid; antiprotozoal agent; atorvastatin; atovaquone; bisphosphonic acid derivative; cerivastatin; compactin; farnesyl diphosphate; geranylgeranyl pyrophosphate; hydroxymethylglutaryl coenzyme A reductase inhibitor; mevinolin; phytoene synthase; pitavastatin; risedronic acid; simvastatin; unclassified drug; zoledronic acid; 3-hydroxy-3-methylglutaryl-coenzyme A; acyl coenzyme A; antiprotozoal agent; atorvastatin; bisphosphonic acid derivative; farnesyl diphosphate; geranyltransferase; hydroxymethylglutaryl coenzyme A reductase; hydroxymethylglutaryl coenzyme A reductase inhibitor; imidazole derivative; isoprenoid phosphate; phytoene synthase; sesquiterpene; zoledronic acid; animal experiment; animal model; Article; controlled study; dose response; drug cytotoxicity; drug dose; drug potentiation; EC50; human; human cell; IC50; in vitro study; in vivo study; infection prevention; low drug dose; mouse; murine toxoplasmosis; nonhuman; priority journal; Toxoplasma gondii; animal; antagonists and inhibitors; biosynthesis; cell line; drug effects; genetics; growth, development and aging; metabolism; Toxoplasma; toxoplasmosis; Acyl Coenzyme A; Animals; Antiprotozoal Agents; Atorvastatin Calcium; Cell Line; Diphosphonates; Geranylgeranyl-Diphosphate Geranylgeranyltransferase; Geranyltranstransferase; Hydroxymethylglutaryl CoA Reductases; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Imidazoles; Mice; Polyisoprenyl Phosphates; Sesquiterpenes; Toxoplasma; Toxoplasmosis
Año:2017
Volumen:61
Número:8
DOI: http://dx.doi.org/10.1128/AAC.02628-16
Título revista:Antimicrobial Agents and Chemotherapy
Título revista abreviado:Antimicrob. Agents Chemother.
ISSN:00664804
CODEN:AMACC
CAS:alendronic acid, 66376-36-1; atorvastatin, 134523-00-5, 134523-03-8; atovaquone, 94015-53-9, 95233-18-4; cerivastatin, 143201-11-0; compactin, 73573-88-3; farnesyl diphosphate, 13058-04-3, 372-97-4; geranylgeranyl pyrophosphate, 6699-20-3; mevinolin, 75330-75-5; phytoene synthase, 50936-61-3, 57219-66-6; pitavastatin, 147526-32-7; risedronic acid, 105462-24-6, 122458-82-6; simvastatin, 79902-63-9; zoledronic acid, 118072-93-8, 131654-46-1, 165800-06-6, 165800-07-7; geranyltransferase, 37277-79-5, 50812-36-7; hydroxymethylglutaryl coenzyme A reductase, 37250-24-1; 3-hydroxy-3-methylglutaryl-coenzyme A; Acyl Coenzyme A; Antiprotozoal Agents; Atorvastatin Calcium; Diphosphonates; farnesyl pyrophosphate; Geranylgeranyl-Diphosphate Geranylgeranyltransferase; Geranyltranstransferase; Hydroxymethylglutaryl CoA Reductases; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Imidazoles; Polyisoprenyl Phosphates; Sesquiterpenes; zoledronic acid
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00664804_v61_n8_p_Li

Referencias:

  • Israelski, D.M., Remington, J.S., Toxoplasmosis in patients with cancer (1993) Clin Infect Dis, 17, pp. S423-S435. , https://doi.org/10.1093/clinids/17.Supplement_2.S423
  • Luft, B.J., Hafner, R., Korzun, A.H., Leport, C., Antoniskis, D., Bosler, E.M., Bourland, D.D., III, Remington, J.S., Toxoplasmic encephalitis in patients with the acquired immunodeficiency syndrome (1993) N Engl J Med, 329, pp. 995-1000. , https://doi.org/10.1056/NEJM199309303291403
  • Wong, S.Y., Remington, J.S., Toxoplasmosis in pregnancy (1994) Clin Infect Dis, 18, pp. 853-861. , https://doi.org/10.1093/clinids/18.6.853
  • Holland, G.N., Ocular toxoplasmosis: A global reassessment. Part II. Disease manifestations and management (2004) Am J Ophthalmol, 137, pp. 1-17. , https://doi.org/10.1016/j.ajo.2003.10.032
  • Neville, A.J., Zach, S.J., Wang, X., Larson, J.J., Judge, A.K., Davis, L.A., Vennerstrom, J.L., Davis, P.H., Clinically available medicines demonstrating anti-Toxoplasma activity (2015) Antimicrob Agents Chemother, 59, pp. 7161-7169. , https://doi.org/10.1128/AAC.02009-15
  • Dyer, O., Company reneges on promise to cut price of toxoplasmosis drug (2015) BMJ, 351, p. h6472. , https://doi.org/10.1136/bmj.h6472
  • Rodriguez, J.B., Szajnman, S.H., New antibacterials for the treatment of toxoplasmosis; a patent review (2012) Expert Opin Ther Pat, 22, pp. 311-333. , https://doi.org/10.1517/13543776.2012.668886
  • Derouin, F., Anti-toxoplasmosis drugs (2001) Curr Opin Investig Drugs, 2, pp. 1368-1374
  • Wei, H.X., Wei, S.S., Lindsay, D.S., Peng, H.J., A Systematic review and meta-analysis of the efficacy of anti-Toxoplasma gondii medicines in humans (2015) PLoS One, 10. , https://doi.org/10.1371/journal.pone.0138204
  • Oldfield, E., Targeting isoprenoid biosynthesis for drug discovery: Bench to bedside (2010) Acc Chem Res, 43, pp. 1216-1226. , https://doi.org/10.1021/ar100026v
  • Nair, S.C., Brooks, C.F., Goodman, C.D., Sturm, A., McFadden, G.I., Sundriyal, S., Anglin, J.L., Striepen, B., Apicoplast isoprenoid precursor synthesis and the molecular basis of fosmidomycin resistance in Toxoplasma gondii (2011) J Exp Med, 208, pp. 1547-1559. , https://doi.org/10.1084/jem.20110039
  • Ling, Y., Li, Z.H., Miranda, K., Oldfield, E., Moreno, S.N., The farnesyl-diphosphate/geranylgeranyl-diphosphate synthase of Toxoplasma gondii is a bifunctional enzyme and a molecular target of bisphosphonates (2007) J Biol Chem, 282, pp. 30804-30816. , https://doi.org/10.1074/jbc.M703178200
  • Li, Z.H., Ramakrishnan, S., Striepen, B., Moreno, S.N., Toxoplasma gondii relies on both host and parasite isoprenoids and can be rendered sensitive to atorvastatin (2013) PLoS Pathog, 9. , https://doi.org/10.1371/journal.ppat.1003665
  • Martin, M.B., Arnold, W., Heath, H.T., III, Urbina, J.A., Oldfield, E., Nitrogen-containing bisphosphonates as carbocation transition state analogs for isoprenoid biosynthesis (1999) Biochem Biophys Res Commun, 263, pp. 754-758. , https://doi.org/10.1006/bbrc.1999.1404
  • Rodan, G.A., Mechanisms of action of bisphosphonates (1998) Annu Rev Pharmacol Toxicol, 38, pp. 375-388. , https://doi.org/10.1146/annurev.pharmtox.38.1.375
  • Russell, R.G., Bisphosphonates: The first 40 years (2011) Bone, 49, pp. 2-19. , https://doi.org/10.1016/j.bone.2011.04.022
  • Reddy, R., Dietrich, E., Lafontaine, Y., Houghton, T.J., Belanger, O., Dubois, A., Arhin, F.F., Rafai Far, A., Bisphosphonated benzoxazinorifamycin prodrugs for the prevention and treatment of osteomyelitis (2008) ChemMedChem, 3, pp. 1863-1868. , https://doi.org/10.1002/cmdc.200800255
  • Miller, K., Erez, R., Segal, E., Shabat, D., Satchi-Fainaro, R., Targeting bone metastases with a bispecific anticancer and antiangiogenic polymer-alendronate-taxane conjugate (2009) Angew Chem Int Ed Engl, 48, pp. 2949-2954. , https://doi.org/10.1002/anie.200805133
  • Sanders, J.M., Ghosh, S., Chan, J.M., Meints, G., Wang, H., Raker, A.M., Song, Y., Oldfield, E., Quantitative structure-activity relationships for gammadelta T cell activation by bisphosphonates (2004) J Med Chem, 47, pp. 375-384. , https://doi.org/10.1021/jm0303709
  • Linares, G.E., Ravaschino, E.L., Rodriguez, J.B., Progresses in the field of drug design to combat tropical protozoan parasitic diseases (2006) Curr Med Chem, 13, pp. 335-360. , https://doi.org/10.2174/092986706775476043
  • Docampo, R., Moreno, S.N., Bisphosphonates as chemotherapeutic agents against trypanosomatid and apicomplexan parasites (2001) Curr Drug Targets Infect Disord, 1, pp. 51-61. , https://doi.org/10.2174/1568005013343191
  • Urbina, J.A., Moreno, B., Vierkotter, S., Oldfield, E., Payares, G., Sanoja, C., Bailey, B.N., Docampo, R., Trypanosoma cruzi contains major pyrophosphate stores, and its growth in vitro and in vivo is blocked by pyrophosphate analogs (1999) J Biol Chem, 274, pp. 33609-33615. , https://doi.org/10.1074/jbc.274.47.33609
  • Martin, M.B., Grimley, J.S., Lewis, J.C., Heath, H.T., III, Bailey, B.N., Kendrick, H., Yardley, V., Oldfield, E., Bisphosphonates inhibit the growth of Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasma gondii, and Plasmodium falciparum: A potential route to chemotherapy (2001) J Med Chem, 44, pp. 909-916. , https://doi.org/10.1021/jm0002578
  • Doggett, J.S., Nilsen, A., Forquer, I., Wegmann, K.W., Jones-Brando, L., Yolken, R.H., Bordon, C., Riscoe, M.K., Endochin-like quinolones are highly efficacious against acute and latent experimental toxoplasmosis (2012) Proc Natl Acad Sci U S A, 109, pp. 15936-15941. , https://doi.org/10.1073/pnas.1208069109
  • (2005) Physicians’ Desk Reference, p. 2585. , Physicians’ Desk Reference. 59th ed, Medical Economics Company, Montvale, NJ
  • Seeber, F., Soldati-Favre, D., Metabolic pathways in the apicoplast of apicomplexa (2010) Int Rev Cell Mol Biol, 281, pp. 161-228. , https://doi.org/10.1016/S1937-6448(10)81005-6
  • Wiesner, J., Reichenberg, A., Heinrich, S., Schlitzer, M., Jomaa, H., The plastid-like organelle of apicomplexan parasites as drug target (2008) Curr Pharm Des, 14, pp. 855-871. , https://doi.org/10.2174/138161208784041105
  • Blader, I.J., Manger, I.D., Boothroyd, J.C., Microarray analysis reveals previously unknown changes in Toxoplasma gondii-infected human cells (2001) J Biol Chem, 276, pp. 24223-24231. , https://doi.org/10.1074/jbc.M100951200
  • Li, Y., Shah-Simpson, S., Okrah, K., Belew, A.T., Choi, J., Caradonna, K.L., Padmanabhan, P., Burleigh, B.A., Transcriptome remodeling in Trypanosoma cruzi and human cells during intracellular infection (2016) PLoS Pathog, 12. , https://doi.org/10.1371/journal.ppat.1005511
  • Recher, M., Barboza, A.P., Li, Z.H., Galizzi, M., Ferrer-Casal, M., Szajnman, S.H., Docampo, R., Rodriguez, J.B., Design, synthesis and biological evaluation of sulfur-containing 1,1-bisphosphonic acids as antiparasitic agents (2013) Eur J Med Chem, 60, pp. 431-440. , https://doi.org/10.1016/j.ejmech.2012.12.015
  • Li, Z.H., Cintron, R., Koon, N.A., Moreno, S.N., The N-terminus and the chain-length determination domain play a role in the length of the isoprenoid product of the bifunctional Toxoplasma gondii farnesyl diphosphate synthase (2012) Biochemistry, 51, pp. 7533-7540. , https://doi.org/10.1021/bi3005335
  • Zhang, Y., Cao, R., Yin, F., Hudock, M.P., Guo, R.T., Krysiak, K., Mukherjee, S., Oldfield, E., Lipophilic bisphosphonates as dual farnesyl/geranylgeranyl diphosphate synthase inhibitors: An X-ray and NMR investigation (2009) J Am Chem Soc, 131, pp. 5153-5162. , https://doi.org/10.1021/ja808285e
  • Van Dooren, G.G., Tomova, C., Agrawal, S., Humbel, B.M., Striepen, B., Toxoplasma gondii Tic20 is essential for apicoplast protein import (2008) Proc Natl Acad Sci U S A, 105, pp. 13574-13579. , https://doi.org/10.1073/pnas.0803862105
  • Pillai, S.K., Moellering, R.C., Eliopoulos, G.M., Antimicrobial combinations (2005) Antibiotics in Laboratory Medicine, pp. 365-440. , Lorian V (ed), 5th ed. Lippincott Williams & Wilkins Co., Philadelphia, PA
  • Berenbaum, M.C., A method for testing for synergy with any number of agents (1978) J Infect Dis, 137, pp. 122-130. , https://doi.org/10.1093/infdis/137.2.122
  • Chou, T.C., Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies (2006) Pharmacol Rev, 58, pp. 621-681. , https://doi.org/10.1124/pr.58.3.10
  • Chou, T.C., Talalay, P., Quantitative analysis of dose-effect relationships: The combined effects of multiple drugs or enzyme inhibitors (1984) Adv Enzyme Regul, 22, pp. 27-55. , https://doi.org/10.1016/0065-2571(84)90007-4
  • Chou, T.C., Martin, N., (2005) CompuSyn for Drug Combinations: PC Software and User’s Guide. A Computer Program for Quantitation of Synergism and Antagonism in Drug Combinations and the Determination of IC50 and Ed50 and LD50 Values, , ComboSyn, Inc., Paramus, NJ

Citas:

---------- APA ----------
Li, Z.-H., Li, C., Szajnman, S.H., Rodriguez, J.B. & Moreno, S.N.J. (2017) . Synergistic activity between statins and bisphosphonates against acute experimental toxoplasmosis. Antimicrobial Agents and Chemotherapy, 61(8).
http://dx.doi.org/10.1128/AAC.02628-16
---------- CHICAGO ----------
Li, Z.-H., Li, C., Szajnman, S.H., Rodriguez, J.B., Moreno, S.N.J. "Synergistic activity between statins and bisphosphonates against acute experimental toxoplasmosis" . Antimicrobial Agents and Chemotherapy 61, no. 8 (2017).
http://dx.doi.org/10.1128/AAC.02628-16
---------- MLA ----------
Li, Z.-H., Li, C., Szajnman, S.H., Rodriguez, J.B., Moreno, S.N.J. "Synergistic activity between statins and bisphosphonates against acute experimental toxoplasmosis" . Antimicrobial Agents and Chemotherapy, vol. 61, no. 8, 2017.
http://dx.doi.org/10.1128/AAC.02628-16
---------- VANCOUVER ----------
Li, Z.-H., Li, C., Szajnman, S.H., Rodriguez, J.B., Moreno, S.N.J. Synergistic activity between statins and bisphosphonates against acute experimental toxoplasmosis. Antimicrob. Agents Chemother. 2017;61(8).
http://dx.doi.org/10.1128/AAC.02628-16