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Analysis of in vitro and in vivo activity of nitroimidazole derivatives against Mycobacterium tuberculosis

Grant number: 20/08370-5
Support type:Scholarships in Brazil - Master
Effective date (Start): June 01, 2021
Effective date (End): February 28, 2022
Field of knowledge:Biological Sciences - Microbiology - Applied Microbiology
Principal researcher:Fernando Rogério Pavan
Grantee:Karyn Fernanda Manieri
Home Institution: Faculdade de Ciências Farmacêuticas (FCFAR). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil

Abstract

Tuberculosis (TB) is an infectious disease whose main etiological agent is Mycobacterium tuberculosis. According to the WHO, cases of death from TB exceed the cases of HIV in the world, about 1.3 million a year. This chronic disease is often asymptomatic, coming to manifest itself only many years after the individual has been infected, thus estimating that about 1/4 of the world population has TB in its asymptomatic form, called latently. TB has a long treatment, consisting of the use of concomitant antibiotics, such as rifampicin (RFP), ethambutol (ETH), pyrazinamide (PZA) and isoniazid (INH), each having a different mechanism of action to prevent the emergence of resistant strains antibiotics. Even so, there is still a serious problem regarding mycobacterial resistance, where for more than 50 years the success of research for new antibiotics has been hampered by the emergence of resistant, multidrug-resistant (MDR-TB) and even extensively resistant strains (DR-TB). Our group has been working for some time and has published some very promising works with benzofuroxan compounds. In this search, we found a leading compound, called BZ8 that obtained, among other promising activities, the ability to 100% inhibit lung infection in BALB/c models. However, BZ8 was not as active in vitro in resistant strains and its chemistry has an N-oxide structure that can be unstable. Pretomanide, formerly known as PA-824, is a compound of the nitroimidazole class, recently approved for use in resistant infections. Our proposal was to develop a hybrid compound between pretomanida and BZ8. The project in question aims to evaluate the activities of these hybrid compounds in vitro and in vivo, using strains of M. tuberculosis in different metabolic conditions, because as is known, the bacillus tends to persist even in hypoxia and intracellular conditions, as well as its toxicity in an alternative model. (AU)

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