Development of methionyl-tRNA synthetase inhibitors of drug-resistant Gram-negative bacteria

• Grant number: 24/11146-0
• Support Opportunities: Scholarships in Brazil - Master
• Start date: December 01, 2024
• End date: July 31, 2026
• Field of knowledge: Health Sciences - Pharmacy
• Principal Investigator: Silvana Aparecida Rocco
• Grantee: Julia Silva Souza
• Host Institution: Centro Nacional de Pesquisa em Energia e Materiais (CNPEM). Ministério da Ciência, Tecnologia e Inovação (Brasil). Campinas , SP, Brazil

Abstract

Infections caused by pathogens that present multiple antimicrobial resistance (AMR) have increased significantly in recent decades, posing a serious threat to human health. AMR has been observed especially in diseases caused by Gram-negative bacteria such as Klebsiella pneumoniae, which causes pneumonia. The presence of a protective layer in these bacteria hinders the permeability of antimicrobials into the cell. An alternative to combat AMR is the development of drugs that inhibit aminoacyl-tRNA synthetases (aaRS), enzymes responsible for protein synthesis, which can be divided into Class 1 and Class 2. The present project aims to develop inhibitors for methionyl-tRNA synthetase Type 2 (MetRS2), an enzyme found mainly in Gram-negative bacteria that functions in the initiation and elongation stages of protein synthesis. Thus, our objectives are to: establish synthesis routes for quinazolin-4(3H)-ones and pyrido[3,2-d]pyrimidin-4-ones derivatives and characterize all compounds using both basic and advanced laboratory techniques; determine the IC50 values for the identified hits and perform orthogonal assays for their validation; and perform in vitro phenotypic assays with Gram-negative bacteria and mammalian cells to evaluate antimicrobial activity and cytotoxicity. The data obtained in this project will allow a better understanding of the dynamics of antibiotic resistance in Gram-negative bacteria, contributing to advances in identifying molecules that exhibit inhibitory activity on methionyl-tRNA synthetase Type 2 (MetRS2). Chemical probes targeting aminoacyl-tRNA synthetases will be available as potential chemotherapies for the development of new antimicrobial agents.