Structural basis of the elongation and cell division control in Mycobacterium tuberculosis and identification of new drug hits based in fragment trials

• Grant number: 16/18721-4
• Support type: Scholarships in Brazil - Doctorate (Direct)
• Effective date (Start): September 01, 2017
• Effective date (End): July 31, 2022
• Field of knowledge: Biological Sciences - Biophysics - Molecular Biophysics
• Principal researcher: Marcio Vinicius Bertacine Dias
• Grantee: Catharina dos Santos Silva
• Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Although the infection caused by Mycobacterium tuberculosis is considered one of the oldest and largely studied disease of humankind, it follows as a leader in both incidence and mortality rates, among bacterial infections. According to the World Health Organization, about 9.6 million of new cases of tuberculosis and 1.5 million of deaths were notified only in 2014. In addition, it is estimated that one third of the worldwide population is infected by the latent form of this pathogen. In this scenario, searching for new treatment strategies to combat the pathogen, in its active and dormant stages, are urgently need. In the scope of structural and functional biology, recent studies have contributed to understanding key mechanisms of M. tuberculosis physiology, as those that include processes of cellular elongation and cell division. Studies about the cellular wall biosynthesis have revealed a synergistic interaction between the endopeptidase RipA and the glycosylase RpfB. However, the complex RipA-RpfB is inhibited by the penicillin binding protein PonA1. This event occurs because PonA1 and RpfB compete for the interaction site of RipA, emerging a post-translational regulatory mechanism of peptidoglycan synthesis and hydrolysis. However, there is no structural data available to aid on the comprehension of such intermolecular interactions and, consequently, the regulatory mechanisms driven from them. In addition, RipA and PonA1 show enzymatic activity and both proteins are essential for the growth and establishment of infection by M. tuberculosis; thus, these enzymes are attractive targets for the development of novel drugs. Therefore, the present research project aims to obtain and structurally characterize the complexes between RipA-RpfB and RipA-PonA1, in order to advance our knowledge about physiological processes in which such proteins are acting. In addition, to contribute on the field of discovery of new antitubercular agents we intend to apply the technique of fragment based drug Discovery targeting RipA and PonA aiming identified new lead molecules. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

RIBEIRO, JOAO AUGUSTO; CHAVEZ-PACHECO, SAIR MAXIMO; DE OLIVEIRA, GABRIEL STEPHANI; SILVA, CATHARINA DOS SANTOS; PIMENTA GIUDICE, JOAO HENRIQUE; LIBREROS-ZUNIGA, GERARDO ANDRES; BERTACINE DIAS, MARCIO VINICIUS. Crystal structures of the closed form of Mycobacterium tuberculosis dihydrofolate reductase in complex with dihydrofolate and antifolates. ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY, v. 75, n. 7, p. 682-693, JUL 2019. Web of Science Citations: 0.

LIBREROS-ZUNIGA, GERARDO ANDRES; SILVA, CATHARINA DOS SANTOS; FERREIRA, RAFAELA SALGADO; BERTACINE DIAS, MARCIO VINICIUS. Structural Basis for the Interaction and Processing of beta-Lactam Antibiotics by L,D-Transpeptidase 3 (Ldt(Mt3)) from Mycobacterium tuberculosis. ACS INFECTIOUS DISEASES, v. 5, n. 2, p. 260-271, FEB 2019. Web of Science Citations: 1.