Synergistic activity between statins and bisphosphonates against acute experimental toxoplasmosis
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 f...
Guardado en:
| Autores principales: | , , , , |
|---|---|
| Formato: | JOUR |
| Materias: | |
| Acceso en línea: | http://hdl.handle.net/20.500.12110/paper_00664804_v61_n8_p_Li |
| Aporte de: |
| id |
todo:paper_00664804_v61_n8_p_Li |
|---|---|
| record_format |
dspace |
| spelling |
todo:paper_00664804_v61_n8_p_Li2023-10-03T14:53:07Z Synergistic activity between statins and bisphosphonates against acute experimental toxoplasmosis Li, Z.-H. Li, C. Szajnman, S.H. Rodriguez, J.B. Moreno, S.N.J. 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 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. JOUR info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar http://hdl.handle.net/20.500.12110/paper_00664804_v61_n8_p_Li |
| institution |
Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-134 |
| collection |
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
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 |
| spellingShingle |
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 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 |
| topic_facet |
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 |
| description |
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. |
| format |
JOUR |
| author |
Li, Z.-H. Li, C. Szajnman, S.H. Rodriguez, J.B. Moreno, S.N.J. |
| author_facet |
Li, Z.-H. Li, C. Szajnman, S.H. Rodriguez, J.B. Moreno, S.N.J. |
| author_sort |
Li, Z.-H. |
| title |
Synergistic activity between statins and bisphosphonates against acute experimental toxoplasmosis |
| title_short |
Synergistic activity between statins and bisphosphonates against acute experimental toxoplasmosis |
| title_full |
Synergistic activity between statins and bisphosphonates against acute experimental toxoplasmosis |
| title_fullStr |
Synergistic activity between statins and bisphosphonates against acute experimental toxoplasmosis |
| title_full_unstemmed |
Synergistic activity between statins and bisphosphonates against acute experimental toxoplasmosis |
| title_sort |
synergistic activity between statins and bisphosphonates against acute experimental toxoplasmosis |
| url |
http://hdl.handle.net/20.500.12110/paper_00664804_v61_n8_p_Li |
| work_keys_str_mv |
AT lizh synergisticactivitybetweenstatinsandbisphosphonatesagainstacuteexperimentaltoxoplasmosis AT lic synergisticactivitybetweenstatinsandbisphosphonatesagainstacuteexperimentaltoxoplasmosis AT szajnmansh synergisticactivitybetweenstatinsandbisphosphonatesagainstacuteexperimentaltoxoplasmosis AT rodriguezjb synergisticactivitybetweenstatinsandbisphosphonatesagainstacuteexperimentaltoxoplasmosis AT morenosnj synergisticactivitybetweenstatinsandbisphosphonatesagainstacuteexperimentaltoxoplasmosis |
| _version_ |
1807324057248464896 |