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Structural and inhibition by beta-lactams studies of LD-transpeptidases from Mycobacterium leprae

Grant number: 20/13103-6
Support type:Scholarships in Brazil - Doctorate (Direct)
Effective date (Start): June 01, 2021
Effective date (End): July 31, 2025
Field of knowledge:Biological Sciences - Biochemistry - Chemistry of Macromolecules
Principal researcher:Marcio Vinicius Bertacine Dias
Grantee:Danilo Pavão e Pavão
Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Leprosy is a chronic infectious disease, caused by Mycobacterium leprae or Hansen´s bacillus, which promotes severe injury to the skin and peripheric nerves and that could lead to physical disability. Brazil figures out as the second country in the number of cases for this disease, which is also strongly associated with low human development indices. Although leprosy has treatment, it requires long-term use of antibiotics (about six months), which has several side effects, and consequently, they have low adhesion to the patients, which contributes to the emerging of resistant strains. Because of the difficulties to work with Hansen´s bacillus, which includes slow growth speed and its inability to grow in in vitro culture, associated with the relationship with poverty, leprosy is considered a neglected disease. Because of that, the pathophysiology of leprosy is still not very well understood and there is a limited literature showing methods aiming to develop new therapies that could shorten the regime treatment and decrease the side effects. In this context, there is no information about the effect of most of ²-lactam on the viability of the bacillus. There is also a total absence of studies with the transpeptidases involved in the bacterium peptidoglycan formation, particularly the LD-transpeptidases, which perform the 3’3 cross-linkages, which are the predominant form in the cell wall of this bacterium. In this project, we aim to perform a complete biophysical and biochemical characterization for the four LD-transpeptidases annotated in the M. leprae genome. We aim to deliver the three-dimensional structures of these proteins in the apo form and, in the presence of ligands and perform a characterization of those ²-lactams that have the highest affinities to these enzymes through calorimetric techniques. We will also obtain the biochemical inhibitory constants using a hydrolysable ²-lactam (nitrocefin) for the most promising ²-lactams. This study, in the end, will have as an outcome those ²-lactams that have the highest potential to be used as alternative drugs to treat leprosy, and consequently contribute for improve life quality of patients. (AU)