Discovery of antimicrobial molecules related to bacterial cell wall formation

• Grant number: 19/13497-7
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: February 01, 2020
• End date: September 30, 2022
• Field of knowledge: Biological Sciences - Biophysics - Molecular Biophysics
• Principal Investigator: Andrea Dessen de Souza e Silva
• Grantee: Caio Cesar de Lima Silva
• Host Institution: Centro Nacional de Pesquisa em Energia e Materiais (CNPEM). Ministério da Ciência, Tecnologia e Inovação (Brasil). Campinas , SP, Brazil
• Associated research grant: 17/12436-9 - ANTIBIO-BAC: exploring the bacterial cell wall as a target for novel antibiotherapies, AP.SPEC

Abstract

The discovery of penicillin in the first half of the 20th century, for the first time, brought the possibility for treating previously intractable infections. Shortly thereafter, there was an era of discovery of several other antimicrobial molecules. However, the increasing appearance of antibiotic-resistant bacteria became a global concern. Therefore, efforts are being made worldwide to understand the molecular mechanisms of antibiotic action and bacterial resistance, but especially in the discovery of new molecules with antimicrobial activity. The Dessen group, in partnership with researchers from Brazil and Europe, has been advancing for years in this search for new antibiotics through the screening of natural products from the still unexplored Brazilian biodiversity. In an initial study, with support from FAPESP, the team identified several compounds with potential for inhibition of Penicillin-Binding Proteins (PBPs), which play an essential role in bacterial cell wall formation and whose inhibition by penicillin and other ²-lactams inhibits growth or promotes bacterial cell lysis. In this project, we will continue the development of this study with PBPs with the dereplication of the 'hits' identified so far, as well as explore new natural sources with the use of biochemical, biophysical and cellular tools developed in the Dessen laboratory. Furthermore, considering the importance of ²-lactamases, bacterial resistance-related enzymes against ²-lactams, we also intend to search for molecules with the ability to inhibit ²-lactamases and, thus, to block their antibiotic-hydrolyzing activities. Due to the structural similarity between their active site and that of PBPs, we plan to carry out inhibition tests with ²-lactamases from antibiotic-resistant bacteria with both hit molecules/extracts identified as inhibitors in screening with PBPs and with extracts from our natural products library. Therewith, we hope to find new molecules that can be used in the development of new treatments, alone or in combination with other molecules, to fight bacterial infections. Although challenging and of high risk, this project may lead to the discovery of new molecules with antimicrobial activity that could be of high impact to combat antibiotic-resistant bacteria. (AU)