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Functional and structural studies of aminoacyl-tRNA synthetases from multi-drug resistant gram-negative bacteria and search for new inhibitors

Abstract

Over the past few decades, the increasing incidence of infections caused by pathogens with multiple antimicrobial resistance (AMR) has become a global health problem. Recent reports from institutions such as the World Health Organization (WHO) and the Centers for Disease Control and Prevention (CDC) point out how Gram-negative bacteria pose a serious threat to human health. Klebsiella pneumoniae is a Gram-negative bacterium that frequently express an AMR phenotype, being considered an opportunistic pathogen that is involved with both nosocomial and community-associated infections. This project aims to study aminoacyl-tRNA synthetases (aaRS) from K. pneumoniae. AaRS are ubiquitous enzymes responsible for the addition of specific amino acids to cognates transporting RNA (tRNA), thus playing an essential role in several biological processes including protein synthetics. Thanks to the evolutionary divergences between aaRS of hosts and pathogens, selective aaRS inhibitors have been described for several infectious organisms. Thus, we aim to perform the biochemical and structural characterization of the enzymes methionyl- and prolyl-tRNA synthetase (MetRS and ProRS, respectively) from K. pneumoniae; to employ high-throughput screening (HTS) and structure-based design for the identification of small molecules (100-500 Daltons) capable of inhibiting the target enzymes; and to carry out phenotypic assays with Gram-negative bacteria and mammalian cells to evaluate antimicrobial activity and toxicity of the inhibitors identified. The data obtained in this project have the potential to expand the knowledge about enzymes considered to be essential for K. pneumoniae, and also to deliver novel inhibitors of the target-enzymes. In addition, biochemical and structural studies will be used to reveal the determinants of binding of the new inhibitors identified for MetRS and ProRS, especially those having novel chemical scaffolds. Ultimately, the new chemical probes identified for the target enzymes will be available for the development of new measures to control drug-resistant Gram-negative bacteria. (AU)

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