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National Institute of Science and Technology on Tuberculosis (INCT-TB) Management committee Diógenes Santiago Santos (Coordinator) Afrânio Lineu Kritski (Vice-coordinator) João Batista Calixto Luiz Gonzaga de França Lopes Reynaldo Dietze Luiz Roberto Ribeiro Castello Branco Main researchers Afrânio Lineu Kritski, Ana Paula Junqueira Kipnis, André Arigony Souto, Anete Trajman, Antônio Ruffino Neto, Christian Macagnan Probst, Diógenes Santiago Santos, Eraldo Batista Junior, Fernanada Carvalho de Mello Queiroz, Hector Ricardo Morbidoni, João Batista Calixto, José Aparício Brites Funck, José Roberto Lapa e Silva, Lee Riley, Leila de Souza Fonseca, Luiz Augusto Basso, Luiz Cláudio Lazzarini de Oliveira, Luiz Gonzaga França, Luiz Roberto Ribeiro castelo Branco, Marcelo Malaghini, Maria Helena Feres Saad, Maria Lúcia Rosa Rossetti , Maria Martha Campos, Martha Maria de Oliveira, Moisés Pallaci, Osmar Norberto de Souza, Pedro Dornelles Picon, Phillip Noel Suffys, Rafael Duarte da Silva, Reynaldo Dietze, Samira Buhrer, Sergio Marcos Arruda, Valeria Cavalcanti Rolla, Vanete Thomaz Soccol, Walter Filgueira de Azevedo Junior, Walter Martin Roland Oleman Main research topics (i) the identification of lead compounds on the basis of defined targets, (ii) the rational development of vaccines, and (iii) the development and validation of new diagnostic methods of drug-susceptible and drugresistant TB and emerging new genotypes. Summary of achievements and perspectives The Minimum Inhibitory Concentration (MIC) for two inorganic complexes: pentacyano(isoniazid)ferrateII (IQG-607) and pentacyano[2-methyl-5(pyridin-4-il)-1,3,4-oxadiazol]ferrateII (IQG639) were determined. Values of 0.25 µg/mL against M. tuberculosis H37Rv laboratorial strain, and 1.00 and 4.00 µg/ml for the isoniazid(INH)-resistant clinical isolates S94A and C(-15)T, respectively, were determined for IQG607. The MICs for IQG-639 were 0.50 µg/ml for the H37Rv strain, and 2.00 and 4.00 µg/mL for the resistant isolates S94A and C(-15)T, respectively. Toxicological evaluation of IQG607 in mice indicates an LD50 value of approximately of 1000 mg/kg. No visible toxic effect was observed following the administration of IQG607 250 mg/kg, according to the observation during 24 h, in either male or female mice. On the other hand, INH at 250 mg/kg oral administration resulted in 80% deaths of mice. Pre-clinical results of in a mouse model of TB whoed that either IQG607 or INH significantly reduced M. tuberculosis-induced splenomegaly. On the other hand, IQG-639 failed to significantly affect this parameter. The spleens and lungs of mice were removed and these organs were homogenized and the colony-forming units (CFU) were determined after 28 days of incubation solid Middlebrook 7H10 medium at 37 °C. Importantly, CFU counting was practically abolished in both spleens and lungs of IQG607- and

INH-treated groups, whereas IQG639 was not capable of reducing CFU numbers. Macroscopic/clinical evaluation of the lungs showed severe alterations in the organs from the infected-non-treated group (Figure 1) when compared to saline group. IQG-607- and INH-treatment seemed to ameliorate the macroscopic aspects of the lungs The proposed objectives in the manufacture of BCG Moreau RDJ batches exclusively for INCT-TB research were achieved. Both oral (FAP medium) and intradermal (Sauton medium) BCG forms can be produced and certified by the Foundation Ataulpho de Paiva (FAP) for the research. Training on quality control of BCG Moreau RDJ (BCG and rBCG) under the supervision of the World Health Organization (WHO) has been obtained by three research centres of INCT-TB (FAP, FIOCRUZ and PUCRS). The development of our research to achieve a new rBCG vaccine against Tuberculosis is guided by the updated WHO recommendation for BCG vaccines. This was recently published at the WHO site:http://www.who. int/biologicals/publications/meetings/areas/vaccines/bcg/BCG_meeting_report_2009v7_FOR_WEB_10JUNE.pdf. Dr Luiz Castello-Branco attended the consultation meeting. In order to comply with international policy approval through STAG (Strategic and Technical Advisory Group from World Health Organization, we carried out the several development (Phase I), and accuracy/interlaboratorial validation (Phase II) studies of phenotypic, serology (with peptides, quimerics proteins, lipids antigens) and molecular prototypes for detection of drug sensitive and drug-resistant TB. More recently, excellent results were obtained in efficacy studies (Phase III) of new brazilian PCR test (Detect TB kit – fig 5) for TB diagnosis in Reference Health Units in Porto Alegre, Rio de Janeiro and Recife. Those results enabled us to establish the first Memorandum Of Understanding (MOU) with private national company in order to scale up the production of needed kits for impact evaluation of the new test in the Health System (Phase IV) pursuing the further approval for National Committee for Technology Incorporation (CITEC) of Ministry of Health and inclusion in the Unified Health System (SUS Main publications Journal of Structural Biology , v. 169, p. 379-388, 2010; Journal of Structural Biology , v. 169, p. 413-423, 2010; Molecular Biosystems , v. 6, p. 967-975, 2010; Archives of Biochemistry and Biophysics , v. 497, p. 35-42, 2010; Bioorganic & Medicinal Chemistry , v. 18, p. 4769-4774, 2010; Journal of Bacteriology , v. 191, p. 2884-2887, 2009; Protein Expression and Purification , v. 66, p. 185-190, 2009; Archives of Biochemistry and Biophysics , v. 486, p. 155-164, 2009; Journal of Biological Macromolecules , v. 45, p. 200-205, 2009; Microbiology (Reading) , v. 155, p. 2652-2663, 2009; Archives of Biochemistry and Biophysics , p. 19-26, 2009; BMC Research Notes , v. 2, p. 227-230, 2009. Contacts E-mail: diogenes.santos@pq.cnpq.br 191

livroinct2010  

Carlos Alberto Aragão de Carvalho Filho Presidente do CNPq 1

livroinct2010  

Carlos Alberto Aragão de Carvalho Filho Presidente do CNPq 1

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