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Mycobacterium cell wall: structural studies and inhibition strategies for enzymes involved in the biosynthesis and regulation

Abstract

The mycobacterium cell wall is a complex and highly regulated structure and proteins involved in its biosynthesis or remodelling can drive the balance between the cell elongation and the cell division. The enzymes involved in the assembly of this complex structure, which is constituted by peptidoglycan, arabinogalactan and mycolic acids, as well the enzymes responsible for its regulation are targets of antimicrobials, such as the ²-lactam or even other antituberculosis drugs; or they are potential candidates for discovery and development of new inhibitory molecules. Thus, understanding how proteins interact to control the biosynthesis cell wall, or how transpeptidases act in catalysing cross-linkage formation in the peptidoglycan has a strong scientific appeal since this information may contribute for developing new strategies to treat tuberculosis. This disease is the major cause of death among infectious diseases and causes the human suffering and death of thousands of people worldwide by year, particularly in countries of Asia, Africa and Latin America, including Brazil. In this project, we are proposing to elucidate the crystallographic structures of classical transpeptidases that catalyse 3-4cross-linkage reactions in the peptidoglycan biosynthesis, particularly the enzymes PonA1 and PonA2 as well as the structural characterization of a non-classical transpeptidase, LD-transpeptidase 4 (LDtMt4), the unique one in a group of five enzymes in which the structure has so far not been determined. This enzyme, in contrast to the classical transpeptidase, is involved in 3-3 cross-linkage formation that is the predominant form in the mycobacterial peptidoglycan. Associated with the structural studies, we will also characterize the interaction of these enzymes with ²-lactam antibiotics through biophysical methods, including isothermal thermodynamic calorimetry. Furthermore, we are also proposing to study the enzymes RipA, RpfB and PonA1 and their protein-protein interactions, which are involved in the regulation of cell wall biosynthesis. We will also use biophysical techniques to understand how these proteins interact. For that, we will use protein crystallography and nuclear magnetic resonance or even other methods if necessary. Finally, for RipA and LDtMt4, we will also apply the technique of fragment-based drug discovery using an in-house library since this protein is a potential target for the development of new drugs against tuberculosis because of its essential role in virulence and viability of Mycobacterium tuberculosis. (AU)

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