Targeting Aminoacyl-tRNA Synthetases of Pathogenic Gram-positive Bacteria To Fight Antibiotic Resistance – BoronTrap

Pathogenic bacteria represent a worldwide public health concern, not only because of the frequency of infections but also because of the phenomena of drug resistance. Today, it is estimated that more than 50% of infections in intensive care units are caused by bacterial pathogens. Here we will focus on Enterococcus faecium and Staphylococcus aureus, which represents a global health problem because it causes severe infections (complicated urinary tract and intraabdominal infections, pneumonia, bloodstream infections or endocarditis). Thus, there is desperate need of new classes of antibacterial drugs, ideally directed to novel targets, to develop the next generation of antibiotics. Benzoxaboroles are novel boron-derived compounds that have gained a big interest, notably with the discovery of the clinically used antifungal kerydin, an inhibitor of leucyl-tRNA synthetase (LeuRS). Here, we will investigate the use of these compounds to treat infections by Gram-positive pathogens listed as WHO top priority. Indeed, data generated by the consortium indicates that benzoxaboroles have activity against these multi-drug resistant bacteria via the inhibition of LeuRS. Here, we propose to target LeuRS of Gram-positive bacteria of the ESKAPE group (S. aureus and E. faecium) to develop novel benzoxaborole-derived antibiotics. Second, given the similarity between the drug binding pocket of LeuRS and IleRS, we will design novel inhibitors of IleRS, or even a dual LeuRS/IleRS inhibitor to hamper the emergence of resistance. We will use a multidisciplinary approach by combining structural biology and biophysical approaches focused on drug discovery with molecular microbiology to provide insights ranging from the atomic scale to the in cellulo level. We believe that the synergy of this interdisciplinary research, involving highly complementary teams, provides the optimal environment to succeed on this project and contribute to accelerate the discovery of next generation antibiotics.