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Visão De Futuro Para Produção De Antibióticos: Tendências De Pesquisa, Desenvolvimento E Inovação

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Visão De Futuro Para Produção De Antibióticos: Tendências De Pesquisa, Desenvolvimento E Inovação UNIVERSIDADE FEDERAL DO RIO DE JANEIRO CRISTINA D’URSO DE SOUZA MENDES SANTOS VISÃO DE FUTURO PARA PRODUÇÃO DE ANTIBIÓTICOS: TENDÊNCIAS DE PESQUISA, DESENVOLVIMENTO E INOVAÇÃO Rio de Janeiro EQ/UFRJ 2014 CRISTINA D ’U RSO DE SOUZA MENDES SANTOS VISÃO DE FUTURO PARA A PRODUÇÃO DE ANTIBIÓTICOS: TENDÊNCIAS DE PESQUISA, DESENVOLVIMENTO E INOVAÇÃO Tese de Doutorado apresentada ao Programa de Pós-Graduação em Tecnologia de Processos Químicos e Bioquímicos, Escola de Química, Universidade Federal do Rio de Janeiro, como requisito parcial à obtenção do título de Doutor em Ciências, D.Sc. Orientadora: Profa. Adelaide Maria de Souza Antunes, D.Sc. Rio de Janeiro 2014 Santos, Cristina d’Urso de Souza Mendes. Visão de futuro para produção de antibióticos: tendências de pesquisa, desenvolvimento e inovação / Cristina d’Urso de Souza Mendes Santos. - Rio de Janeiro, 2014. 216 f.: il.; 29,7 cm. Tese (Doutorado em Ciências) – Universidade Federal do Rio de Janeiro, Escola de Química, Programa de Pós-Graduação em Tecnologia de Processos Químicos e Bioquímicos, Rio de Janeiro, 2014. Orientadora: Adelaide Maria de Souza Antunes. 1. Antibióticos. 2. P&D na Indústria Farmacêutica. 3. Prospecção Tecnológica. 4. Patentes. I. Antunes, Adelaide Maria de Souza. II. Universidade Federal do Rio de Janeiro. Escola de Química. III. Visão de futuro para a produção de antibióticos: tendências de pesquisa, desenvolvimento e inovação. iv v Dedico esta tese à minha mãe querida e amada, que está no céu comemorando esta vitória, que é mais dela do que minha. Dedico também à minha filhinha Malu que sem entender foi a minha maior motivação para concluir esta tese. vi AGRADECIMENTOS Primeiramente, agradeço à minha mãe Emilia (in memoriam ) que durante toda a vida se sacrificou por mim e me incentivou para que eu conseguisse atingir os meus objetivos, um dos quais esta tese. À minha filhinha Malu, pelos fins de semana e momentos em que a mamãe não pôde estar presente para brincar ou sair com ela pois estava estudando. Ao meu marido e companheiro, Marcus, que foi a pessoa chave neste processo todo, para que eu pudesse estudar com tranquilidade. Agradeço por entender, me apoiar e me ajudar nos momentos em que eu não podia estar presente. Ao meu pai que sempre me instigou com conversas intelectuais, filosóficas que foram a base de pensamento crítico fundamental para desenvolver uma tese de doutorado. Além é claro do conserto de computadores de emergência fundamentais para que o trabalho não parasse. À minha orientadora, chefe, colega de trabalho e amiga, Adelaide Antunes que não deixou de jeito nenhum que eu desistisse ou desanimasse apesar de todas as adversidades. Além disso, sua orientação foi fundamental para elaboração e execução desta tese. À minha irmã Luciana e ao meu irmão Felipe, que viveram momentos difíceis comigo, mas que foram meus alicerces nesses momentos, e me deram apoio fundamental para que continuasse o estudo da tese. Agradeço especialmente à minha irmã que resolveu sozinha várias burocracias de inventário, obra, aluguel, etc.... para que eu pudesse terminar a tese. À Lais, que se mostrou mais que uma sogra, uma mãe, cujo apoio, carinho e dedicação foram muito importantes para a elaboração e conclusão desta tese. À Marieta, minha segunda mãe, que sempre esteve presente cuidando de mim e da minha filha em todos os momentos que precisei. Aos membros da banca pelo tempo disponibilizado para leitura e análise deste trabalho. Ao INPI e aos meus antigos chefes, Lucy Mary Gonzalez Gullo e Raul Suster, pelo apoio para iniciar o doutorado e pela liberação de 20 horas para que pudesse fazer o doutorado. vii Aos meus colegas de trabalho do INPI Bernardo Nunes, Priscila Rohem, Rafaela Guerrante, Alexandre Lopes pelas diversas discussões técnicas que foram de grande valia para a elaboração da tese. Aos meus amigos do SIQUIM sempre dispostos a ajudar, em especial: à Priscila Araújo pela ajuda nas correções, à Suzane Rodrigues e ao Pedro Martins pelo apoio administrativo. Aos amigos, que me ajudaram, me deram apoio emocional em momentos difíceis e que me incentivaram em todos os momentos desta jornada. Por fim, agradeço a Deus por ter colocados tantas pessoas especiais no meu caminho, por me dar tudo o necessário para a construção desta tese. viii "O êxito da vida não se mede pelo caminho que você conquistou, mas sim pelas dificuldades que superou no caminho.” Abraham Lincoln “É exatamente disso que a vida é feita, de momentos. Momentos que temos que passar, sendo bons ou ruins, para o nosso próprio aprendizado. Nunca esquecendo do mais importante: Nada nessa vida é por acaso. Absolutamente nada. Por isso, temos que nos preocupar em fazer a nossa parte, da melhor forma possível. A vida nem sempre segue a nossa vontade, mas ela é perfeita naquilo que tem que ser.” Chico Xavier ix RESUMO SANTOS, Cristina d’Urso de Souza Mendes. Visão de futuro para produção de antibióticos: tendências de pesquisa, desenvolvimento e inovação . Tese (Doutorado) - Escola de Química, Universidade Federal do Rio de Janeiro. Orientadora: Prof.ª. Adelaide Mª. S. Antunes. Rio de Janeiro, 2014. A resistência bacteriana cada vez maior e a consequente diminuição da efetividade dos medicamentos acarretam uma necessidade crítica para o desenvolvimento de novos antibióticos. Neste sentido, a presente tese apresenta uma visão de futuro dos antibióticos a partir mapeamento dos novos fármacos nas diferentes etapas do processo de P&D, analisando-os de acordo com sua estrutura química, mecanismo de ação e atividade. Para mapear a demanda por novos antibióticos, em um primeiro momento são identificadas as bactérias patogênicas de maior preocupação no Brasil e no mundo, a saber: a família Enterobacteriaceae, Clostridium difficile , Neisseria gonorrhoeae , Salmonella spp., Staphylococcus aureus , Pseudomonas spp., Shigella spp., Enterococcus spp., Streptococcus pneumoniae , Acinetobacter spp., Campylobacter spp. e Micobacterium tuberculosis . A construção da visão de futuro de novos antibióticos engloba o desenvolvimento de uma metodologia para identificação dos pedidos de patente primários de novos antibióticos, assim como uma metodologia para o mapeamento do seu pipeline das empresas que atuam em P&D de novos antibióticos. A metodologia desenvolvida permitiu: A) a análise das estratégias utilizadas para descoberta de novos antibióticos: triagem na natureza; estratégias de síntese e modificação de classes existentes. B) a identificação e análise dos 1333 pedidos de patente primários onde observa-se que o desenvolvimento de compostos em classes químicas existentes ainda é muito utilizado. Em relação às novas classes com novos mecanismos de ação, destacam-se os antibióticos que inibem a síntese de ácidos graxos e os inibidores da formação de lipopolissacarídeos em bactérias Gram-negativas. Em relação ao espectro de ação dos novos antibióticos nas patentes primárias observa-se um número maior de pedidos de patentes voltados exclusivamente para bactérias Gram- positivas. No entanto, foram identificadas algumas novas classes de antibióticos voltadas somente para Gram-negativos. C) A metodologia desenvolvida permitiu, ainda a identificação dos compostos em fase de testes clínicos onde observa-se que grande parte dos novos antibióticos são modificações de classes existentes, existem novas classes, porém voltadas principalmente para tratamento de infecções por Gram-positivas ou do trato respiratório. Poucos antibióticos em testes clínicos são ativos contra bactérias Gram- negativas. O que faz destas bactérias o ponto crítico para desenvolvimento de novos antibióticos. Tendo em vista este cenário, o grande desafio é transformar os pedidos de patente identificados em novos antibióticos no mercado para o combate às infecções bacterianas cada vez mais resistentes. x ABSTRACT SANTOS, Cristina d’Urso de Souza Mendes. Visão de futuro para produção de antibióticos: tendências de pesquisa, desenvolvimento e inovação. Thesis (Doctor of Science - D.Sc.). - Escola de Química, Universidade Federal do Rio de Janeiro. Adviser: Profª. Adelaide Maria. S. Antunes. Rio de Janeiro, 2014. The increasing bacterial resistance and consequent decrease in the effectiveness of antibiotics cause a critical need for the development of new compounds. In this sense, this thesis presents a vision of future of antibiotics by mapping the new antibiotics in the different stages of the R&D process, analyzing them according to their chemical structure, mechanism of action and activity. In order to map out the demand for new antibiotics, the pathogenic bacteria of higher concern in Brazil and in the world were identified, namely: Enterobacteriaceae, Clostridium difficile , Neisseria gonorrhoeae, Salmonella spp, Staphylococcus aureus , Pseudomonas spp, Shigella, Enterococcus. spp, Streptococcus pneumoniae , Acinetobacter spp, Campylobacter spp, and Mycobacterium tuberculosis . The construction of the vision of the future of new antibiotics involved the development of a methodology for the identification of the primary patent applications of new antibiotics, as well as a methodology for identification of the companies engaged in R&D of new antibiotics and mapping out its pipeline. The methodology developed enabled: A) an analysis of the strategies used for the discovery of new antibiotics: screening in nature; synthesis and modification of existing classes. B) the identification and analysis of 1333 primary patent applications of new antibiotics. It is observed that the development of new compounds in existing chemical classes is still widely
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