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Synergistic Activity between Statins and Bisphosphonates against Acute Experimental Toxoplasmosis.

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 ?M). 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.

SUBMITTER: Li ZH

PROVIDER: S-EPMC5527628 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Synergistic Activity between Statins and Bisphosphonates against Acute Experimental Toxoplasmosis.

Li Zhu-Hong ZH Li Catherine C Szajnman Sergio H SH Rodriguez Juan B JB Moreno Silvia N J SNJ

Antimicrobial agents and chemotherapy 20170725 8

Bisphosphonates are widely used for the treatment of bone disorders. These drugs also inhibit the growth of a variety of protozoan parasites, such as <i>Toxoplasma gondii</i>, 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 <i>T. gondii</i>, we investigated the potential syne ...[more]

PMID: 28559264

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Project description:The control of toxoplasmosis, a rampant one health disease, has been focussed on conventional antitoxoplasmic agents with their adverse outcomes, including serious side effects, treatment failure and emergence of drug resistant strains. Nanobiotechnology may provide a strong impetus for versatile alternative therapies against toxoplasmosis. Bionanofactory Ochrobactrum sp. strain CNE2 was recruited for the biosynthesis of functionalized magnetite iron nanoparticles (MNPs) and nanozerovalent iron (nZVI) under aerobic and anaerobic conditions and their therapeutic efficacy was evaluated against acute toxoplasmosis in murine model. The formation of self-functionalized spherical nanoparticles varied in size, identity and surface properties were substantiated. Mice were orally administered 20 mg/kg of each formulation on the initial day of infection and continued for seven consecutive days post infection (PI). Parasitological, ultrastructural, immunological, and biochemical studies were performed for assessment of therapeutic activity of biogenic iron nanoparticles (INPs). Parasitologically, MNPs showed the highest antitoxoplasmic efficacy in terms of 96.82% and 91.87% reduction in mean tachyzoite count in peritoneal fluid and liver impression smears, respectively. Lesser percentage reductions were recorded in nZVI-treated infected subgroup (75.44% and 69.04%). In addition, scanning electron microscopy (SEM) examination revealed remarkable reduction in size and extensive damage to the surface of MNPs-treated tachyzoites. MNPs-treated infected mice revealed a statistically significant increase in the serum levels of both interferon gamma (IFN-γ) to 346.2 ± 4.6 pg/ml and reduced glutathione (GSH) to 8.83 ± 0.30 mg/dl that subsequently exerted malondialdehyde (MDA) quenching action. MNPs showed a superior promising antitoxoplasmic activity with respect to both spiramycin (SPI) and nZVI. To best of our knowledge, this is the first study of a bio-safe oral iron nanotherapeutic agent fabricated via an eco-friendly approach that offers promising potential against acute experimental toxoplasmosis.

Dataset Information

Synergistic Activity between Statins and Bisphosphonates against Acute Experimental Toxoplasmosis.

Publications

Synergistic Activity between Statins and Bisphosphonates against Acute Experimental Toxoplasmosis.

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