Sample records for amebicides
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Santos, Israel Gomes de Amorim; Scher, Ricardo; Rott, Marilise Brittes; Menezes, Leociley Rocha; Costa, Emmanoel Vilaça; Cavalcanti, Sócrates Cabral de Holanda; Blank, Arie Fitzgerald; Aguiar, Jaciana dos Santos; da Silva, Teresinha Gonçalves; Dolabella, Silvio Santana
2016-02-01
Amoebic keratitis and granulomatous amoebic encephalitis are caused by some strains of free-living amoebae of the genus Acanthamoeba. In the case of keratitis, one of the greatest problems is the disease recurrence due to the resistance of parasites, especially the cystic forms, to the drugs that are currently used. Some essential oils of plants have been used as potential active agents against this protist. Thus, the aim of this study was to determine the amebicidal activity of essential oils from plants of the genus Lippia against Acanthamoeba polyphaga trophozoites. To that end, 8 × 10(4) trophozoites were exposed for 24 h to increasing concentrations of essential oils from Lippia sidoides, Lippia gracilis, Lippia alba, and Lippia pedunculosa and to their major compounds rotundifolone, carvone, and carvacrol. Nearly all concentrations of oils and compounds showed amebicidal activity. The IC50 values for L. sidoides, L. gracilis L. alba, and L. pedunculosa were found to be 18.19, 10.08, 31.79, and 71.47 μg/mL, respectively. Rotundifolone, carvacrol, and carvone were determined as the major compounds showing IC50 of 18.98, 24.74, and 43.62 μg/mL, respectively. With the exception of oil from L. alba, the other oils evaluated showed low cytotoxicity in the NCI-H292 cell line. Given these results, the oils investigated here are promising sources of compounds for the development of complementary therapy against amoebic keratitis and granulomatous amoebic encephalitis and can also be incorporated into cleaning solutions to increase their amebicidal efficiency.
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In Vitro Efficacy of Ebselen and BAY 11-7082 Against Naegleria fowleri.
Debnath, Anjan; Nelson, Andrew T; Silva-Olivares, Angélica; Shibayama, Mineko; Siegel, Dionicio; McKerrow, James H
2018-01-01
Primary amebic meningoencephalitis (PAM) is a fatal infection caused by the free-living ameba Naegleria fowleri , popularly known as the "brain-eating ameba." The drugs of choice in treating PAM are the antifungal amphotericin B and an antileishmanial miltefosine, but these are not FDA-approved for this indication and use of amphotericin B is associated with severe adverse effects. Moreover, very few patients treated with the combination therapy have survived PAM. Therefore, development of efficient drugs is a critical unmet need to avert future deaths of children. Since N. fowleri causes extensive inflammation in the brain it is important to select compounds that can enter brain to kill ameba. In this study, we identified two central nervous system (CNS) active compounds, ebselen and BAY 11-7082 as amebicidal with EC 50 of 6.2 and 1.6 μM, respectively. The closely related BAY 11-7085 was also found active against N. fowleri with EC 50 similar to BAY 11-7082. We synthesized a soluble ebselen analog, which had amebicidal activity similar to ebselen. Transmission electron microscopy of N. fowleri trophozoites incubated for 48 h with EC 50 concentration of ebselen showed alteration in the cytoplasmic membrane, loss of the nuclear membrane, and appearance of electron-dense granules. Incubation of N. fowleri trophozoites with EC 50 concentrations of BAY 11-7082 and BAY 11-7085 for 48 h showed the presence of large lipid droplets in the cytoplasm, disruption of cytoplasmic and nuclear membranes and appearance of several vesicles and chromatin residues. Blood-brain barrier permeable amebicidal compounds have potential as new drug leads for Naegleria infection.
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In Vitro Efficacy of Ebselen and BAY 11-7082 Against Naegleria fowleri
Debnath, Anjan; Nelson, Andrew T.; Silva-Olivares, Angélica; Shibayama, Mineko; Siegel, Dionicio; McKerrow, James H.
2018-01-01
Primary amebic meningoencephalitis (PAM) is a fatal infection caused by the free-living ameba Naegleria fowleri, popularly known as the “brain-eating ameba.” The drugs of choice in treating PAM are the antifungal amphotericin B and an antileishmanial miltefosine, but these are not FDA-approved for this indication and use of amphotericin B is associated with severe adverse effects. Moreover, very few patients treated with the combination therapy have survived PAM. Therefore, development of efficient drugs is a critical unmet need to avert future deaths of children. Since N. fowleri causes extensive inflammation in the brain it is important to select compounds that can enter brain to kill ameba. In this study, we identified two central nervous system (CNS) active compounds, ebselen and BAY 11-7082 as amebicidal with EC50 of 6.2 and 1.6 μM, respectively. The closely related BAY 11-7085 was also found active against N. fowleri with EC50 similar to BAY 11-7082. We synthesized a soluble ebselen analog, which had amebicidal activity similar to ebselen. Transmission electron microscopy of N. fowleri trophozoites incubated for 48 h with EC50 concentration of ebselen showed alteration in the cytoplasmic membrane, loss of the nuclear membrane, and appearance of electron-dense granules. Incubation of N. fowleri trophozoites with EC50 concentrations of BAY 11-7082 and BAY 11-7085 for 48 h showed the presence of large lipid droplets in the cytoplasm, disruption of cytoplasmic and nuclear membranes and appearance of several vesicles and chromatin residues. Blood-brain barrier permeable amebicidal compounds have potential as new drug leads for Naegleria infection. PMID:29559968
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Drug Design Relating Amebicides to Inhibition of Protein Synthesis.
1977-09-01
A study of the effect of emetine on protein synthesis in E. histolytica was made on log phase amebas as compared to stationary phase amebas ...Sensitivity to emetine was maintained independently of the rate of protein synthesis. Furthermore, both stages of amebas had the same capacity to bind emetine...elongation site. Finally, evidence was obtained that the capacity to bind emetine provides a basis for conferring drug resistance in amebas . A direct
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Ergüden, Ceren; Özkoç, Soykan; Öztürk, Bintuğ; Bayram Delibaş, Songül
2016-10-01
Acanthamoeba species are free living amoeba found widely all over the world. They are responsible for Acanthamoeba keratitis (AK), an infection which is especially seen in contact lens users and after minor corneal traumas, that may lead blindness. At present, antifungals and antiseptics are used for the treatment of AK cases, however, some problems such as long treatment periods and the occurrence of side effects, resistance of cyst forms against drugs, emphasize the need for new drugs. There are some published studies that pointed out the effectiveness of plant extracts and essential oils on Acanthamoeba spp. The aim of this study was to investigate the in vitro effects of essential oils of Mentha x piperita L. (peppermint), Melissa officinalis L. (lemon balm) and Ocimum basilicum L. (basil) belonging to Lamiaceae family, on the cysts and trophozoites of Acanthamoeba castellanii. The strain used in our study, namely A. castellanii T4 genotype, is the most frequently isolated amoeba from environment and also the causative agent of AK and granulomatous amebic encephalitis. For the determination of amebicidal activity, essential oils obtained from Mentha x priperita L., Melissa officinalis L. and Ocimum basilicum L. by Neo-Clevenger type of distillation apparatus have been used. In vitro experiments were performed by using 96-well microplates. Cyst and trophozoite solutions were added on the essential oil dilutions to obtain the last concentrations of 40, 20, 10, 5, 2.5 and 1.25 µg/ml for the cysts, and 10, 5, 2.5, 1.25, 0.625 and 0.313 µg/ml for the trophozoites. After the incubation of microplates at 30oC for 1, 6, 24, 48 and 72 hours, the viability of parasitic forms were evaluated under the light microscope followed by staining trypan blue. It was found that, each essential oil showed amebicidal effect on A.castellani cysts and trophozoites dependent on dosage and time, when compared with the control group, The maximum lethal effect occured with Melissa officinalis followed by Mentha x piperita and Ocimum basilicum, respectively. In our study, susceptibility of A.castellanii trophozoites to essential oils were more than the cysts, as expected. The essential oils of Melissa officinalis and Mentha x piperita showed 100% lethal effect at their highest concentrations whereas the essential oil of Ocimum basilicum showed only 63.3% lethal effect on cysts after 72 hours at the highest concentration (40 µg/mL). The results of this first study investigating the activities of essential oils extracted from Mentha x piperita, Melissa officinalis and Ocimum basilicum against Acanthamoeba spp. cysts and trophozoites, have suggested that, these essential oils could be potential novel and alternative natural products for the treatment of Acanthamoeba spp. infections.
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Yang, Wei; Hosford, Sarah R; Traphagen, Nicole A; Shee, Kevin; Demidenko, Eugene; Liu, Stephanie; Miller, Todd W
2018-03-01
Hyperactivation of the PI3K pathway has been implicated in resistance to antiestrogen therapies in estrogen receptor α (ER)-positive breast cancer, prompting the development of therapeutic strategies to inhibit this pathway. Autophagy has tumor-promoting and -suppressing roles and has been broadly implicated in resistance to anticancer therapies, including antiestrogens. Chloroquine (CQ) is an antimalarial and amebicidal drug that inhibits autophagy in mammalian cells and human tumors. Herein, we observed that CQ inhibited proliferation and autophagy in ER + breast cancer cells. PI3K inhibition with GDC-0941 (pictilisib) induced autophagy. Inhibition of autophagy using CQ or RNA interference potentiated PI3K inhibitor-induced apoptosis. Combined inhibition of PI3K and autophagy effectively induced mitochondrial membrane depolarization, which required the BH3-only proapoptotic proteins Bim and PUMA. Treatment with GDC-0941, CQ, or the combination, significantly suppressed the growth of ER + breast cancer xenografts in mice. In an antiestrogen-resistant xenograft model, GDC-0941 synergized with CQ to provide partial, but durable, tumor regression. These findings warrant clinical evaluation of therapeutic strategies to target ER, PI3K, and autophagy for the treatment of ER + breast cancer.-Yang, W., Hosford, S. R., Traphagen, N. A., Shee, K., Demidenko, E., Liu, S., Miller, T. W. Autophagy promotes escape from phosphatidylinositol 3-kinase inhibition in estrogen receptor-positive breast cancer.
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Hsp90 Inhibitors as New Leads To Target Parasitic Diarrheal Diseases
Shahinas, Dea; Bryant, Clifford; Hirata, Ken; Miyamoto, Yukiko; Hwang, Grace; Gut, Jiri; Renslo, Adam R.; Pillai, Dylan R.; Eckmann, Lars; Reed, Sharon L.; McKerrow, James H.
2014-01-01
Entamoeba histolytica and Giardia lamblia are anaerobic protozoan parasites that cause amebiasis and giardiasis, two of the most common diarrheal diseases worldwide. Current therapy relies on metronidazole, but resistance has been reported and the drug has significant adverse effects. Therefore, it is critical to search for effective, better-tolerated antiamebic and antigiardial drugs. We synthesized several examples of a recently reported class of Hsp90 inhibitors and evaluated these compounds as potential leads for antiparasitic chemotherapy. Several of these inhibitors showed strong in vitro activity against both E. histolytica and G. lamblia trophozoites. The inhibitors were rescreened to discriminate between amebicidal and giardicidal activity and general cytotoxicity toward a mammalian cell line. No mammalian cytotoxicity was found at >100 μM for 48 h for any of the inhibitors. To understand the mechanism of action, a competitive binding assay was performed using the fluorescent ATP analogue bis-ANS (4,4′-dianilino-1,1′-binaphthyl-5,5′-disulfonic acid dipotassium salt) and recombinant E. histolytica Hsp90 preincubated in both the presence and absence of Hsp90 inhibitors. There was significant reduction in fluorescence compared to the level in the control, suggesting that E. histolytica Hsp90 is a selective target. The in vivo efficacy and safety of one Hsp90 inhibitor in a mouse model of amebic colitis and giardiasis was demonstrated by significant inhibition of parasite growth at a single oral dose of 5 mg/kg of body weight/day for 7 days and 10 mg/kg/day for 3 days. Considering the results for in vitro activity and in vivo efficacy, Hsp90 inhibitors represent a promising therapeutic option for amebiasis and giardiasis. PMID:24820073
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Allosteric Inhibition of Human Porphobilinogen Synthase*
Lawrence, Sarah H.; Ramirez, Ursula D.; Selwood, Trevor; Stith, Linda; Jaffe, Eileen K.
2009-01-01
Porphobilinogen synthase (PBGS) catalyzes the first common step in tetrapyrrole (e.g. heme, chlorophyll) biosynthesis. Human PBGS exists as an equilibrium of high activity octamers, low activity hexamers, and alternate dimer configurations that dictate the stoichiometry and architecture of further assembly. It is posited that small molecules can be found that inhibit human PBGS activity by stabilizing the hexamer. Such molecules, if present in the environment, could potentiate disease states associated with reduced PBGS activity, such as lead poisoning and ALAD porphyria, the latter of which is associated with human PBGS variants whose quaternary structure equilibrium is shifted toward the hexamer (Jaffe, E. K., and Stith, L. (2007) Am. J. Hum. Genet. 80, 329–337). Hexamer-stabilizing inhibitors of human PBGS were identified using in silico prescreening (docking) of ∼111,000 structures to a hexamer-specific surface cavity of a human PBGS crystal structure. Seventy-seven compounds were evaluated in vitro; three provided 90–100% conversion of octamer to hexamer in a native PAGE mobility shift assay. Based on chemical purity, two (ML-3A9 and ML-3H2) were subjected to further evaluation of their effect on the quaternary structure equilibrium and enzymatic activity. Naturally occurring ALAD porphyria-associated human PBGS variants are shown to have an increased susceptibility to inhibition by both ML-3A9 and ML-3H2. ML-3H2 is a structural analog of amebicidal drugs, which have porphyria-like side effects. Data support the hypothesis that human PBGS hexamer stabilization may explain these side effects. The current work identifies allosteric ligands of human PBGS and, thus, identifies human PBGS as a medically relevant allosteric enzyme. PMID:19812033