14th ICID - Poster Abstracts - International Society for Infectious ...

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When citing these abstracts please use the following reference: Author(s) of abstract. Title of abstract [abstract]. Int J Infect Dis 2010;14S1: Abstract number. Please note that the official publication of the International Journal of Infectious Diseases 2010, Volume 14, Supplement 1 is available electronically on http://www.sciencedirect.com Final Abstract Number: 82.011 Session: Trypanosomiasis, Leishmaniasis & Schistosomiasis Date: Friday, March 12, 2010 Time: 12:30-13:30 Room: Poster & Exhibition Area/Ground Level Type: Poster Presentation Propolis and derivatives of megazol: In vitro and in vivo activity on Trypanosoma cruzi, mechanism of action and selectivity K. Salomão 1 , E. M. De Souza 2 , H. S. Barbosa 1 , S. L. de Castro 3 1 Instituto Oswaldo Cruz, Rio de Janeiro, Rio de Janeiro, Brazil, 2 Instituto Oswaldo Cruz- FIOCRUZ, Rio de Janeiro, Brazil, 3 Fundação Oswaldo Cruz, Rio de Janeiro, Brazil Background: One hundred years after its discovery, Chagas disease, caused by Trypanosoma cruzi, still represents an important health problem and in need of alternative drugs for the treatment of chagasic. Methods: Ethanolic extract of Brazilian green propolis (Et-Bra) was assayed on amastigotes proliferation, trypomastigote by transmission and scanning electron microscopy and flow cytometry. Thirty two 1,3,4-thiadiazole-2-arilhyldrazones of megazol were synthesized and assayed on trypomastigotes. Results: Et-Bra was active against amastigotes proliferation inside mammalian macrophages and induced plasma membrane damage in the infective trypomastigote forms as determined by transmission and scanning electron microscopy and flow cytometry. In non-infected mice, propolis induced no toxicity as determined by the GPT, GOT and CK plasma levels. Treatment of T. cruzi-infected mice (up to 300 mg Et-Bra/kg/day for 10 days) led to a significant reduction of the mortality but not of the parasitemia, did not reversed the hepatic, renal or muscular damage induced by the parasite. The most active analogues in vitro -S1 to S8- were assayed in vivo by a single oral dose at 5 dpi, being selected S1, S2 and S3, together with megazol for subsequent in vitro and in vivo studies. In trypomastigotes, ultrastructural analysis revealed that the compounds led to alterations at kDNA, mitochondrion and flagellar membrane and rounding and torsion of the parasite´s body. S1 and S2 inhibited the amastigotes proliferation inside macrophages, while in cardiac muscular cells only S1 was active. The administration of 10 consecutive doses (50 and 100 mg/kg) of S1 caused no effect on the course of infection, while S2 led to a significant decrease of the parasitemia and S3, only of the mortality. The three analogues were not toxic for the animals based on the levels of GPT, GOT and urea. Conclusion: Our results demonstrate the promising activity on T. cruzi, especially S2 and S3, justifying in vivo assays with longer period of treatment and the continuity of the investigation of new analogues.
When citing these abstracts please use the following reference: Author(s) of abstract. Title of abstract [abstract]. Int J Infect Dis 2010;14S1: Abstract number. Please note that the official publication of the International Journal of Infectious Diseases 2010, Volume 14, Supplement 1 is available electronically on http://www.sciencedirect.com Final Abstract Number: 82.012 Session: Trypanosomiasis, Leishmaniasis & Schistosomiasis Date: Friday, March 12, 2010 Time: 12:30-13:30 Room: Poster & Exhibition Area/Ground Level Type: Poster Presentation Alanine 163 in loop C of Leishmania major aquaglyceroporin LmAQP1 resides near the pore mouth of the channel Y. zhou 1 , G. Mandal 1 , V. S. R. Atluri 1 , E. Beitz 2 , R. Mukhopadhyay 1 1 Florida Internatonal University, Miami, FL, USA, 2 University of Kiel, Gutenbergstrasse, Germany Background: The Leishmania major aquaglyceroporin, LmAQP1, is responsible for the transport of trivalent metalloids, arsenite and antimonite. We have earlier shown that down regulation of LmAQP1 provides resistance to trivalent antimony compounds whereas upregulation of LmAQP1 in drug resistant parasites can reverse the resistance. We have implicated this transporter to volume regulation and osmotaxis, two important characteristics for successful infection. Recently we have shown that a single change in the loop C of LmAQP1 changes its substrate specificity. Beitz et al (2004) have shown that E125 in loop C of PfAQP is close to the mouth of the pore and is critical for high water permeability of PfAQP (Beitz, 2004). Loop C of PfAQP is twelve residues shorter than LmAQP1. Therefore, E125 of PfAQP lines up with A163 in the primary sequence. To confirm that A163 is near the pore mouth we have created different mutants of LmAQP1 and their transport properties were compared. Methods: Different mutants of A163 were created using site directed mutagenesis method. Wild type and mutant LmAQP1 were transfected into wild type L. donovani. Metalloid sensitivity, transport and osmoregulation ability of the transfected parasites were measured. cRNA of wild type and mutated LmAQP1 were injected into Xenopus levis oocytes followed by the determination of metalloid, water and solute transport. Results: Change of A163 to glutamate, glutamine or aspartate made it impermeable to water, metalloids and other solutes. However, changes to serine and threonine did not change the transport properties of the channel. Water transport through LmAQP1 is mercurial insensitive. Introducing cysteine (s) in loop C in the vicinity of A163 made the water transport through the channel mercurial sensitive. Conclusion: We report that A163 in loop C is localized near the pore mouth of LmAQP1.
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