Discovery of compounds that interact with MurE from Mycobacterium tuberculosis using fragment screening

Abstract

Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis that affects about around 10 million people per year worldwide, being a leading cause of death from infectious disease. The therapy used to treat tuberculosis is complex and requires at least 3 different relatively toxic drugs for a period of approximately 6 months, which facilitates patient withdrawal and the emergence of resistant strains. However, only recently, after a period of about 40 years, two new drugs were introduced on the market for the treatment of multidrug-resistant tuberculosis. Thus, new strategies for therapy against tuberculosis are necessary and the peptidoglycan biosynthesis of the cell wall from of Mycobacterium tuberculosis has presented interesting targets for the development of new drugs, since this is an essential process for the mycobacteria survival of the mycobacteria. Thus, the MurE enzyme of Mycobacterium tuberculosis (MtMurE), which is an ATP-dependent ligase and participates in the formation of UDP-MurNac-Pentapeptide in the cytoplasm, is an essential and viable target for the development of new drugs. This enzyme is involved in the first steps of peptidoglycan biosynthesis, but has been virtually unexplored as a target for the development of drugs, especially considering from a structural point of view. Therefore, in this project, we expect intend to perform the identification of compounds that interact with MtMurE through the application of the technique of fragment- based drug discovery. For this, the overexpression of the enzyme will be performed in a heterologous system and it will be purified using affinity and gel filtration columns. Subsequently, MtMurE will be screened against a library of low molecular weight molecules. Attempts to obtain MtMurE structure from the in complexes formed with the identified molecules will be performed. The results obtained in this project will be the starting point for the synthesis of compounds that have inhibitory activity for MtMurE and candidates for the development of new molecules with antituberculosis activity.