Abstract Description

Antimicrobial resistance has become an increasing challenge globally. From the Bacterial Priority Pathogen List published by the World Health Organization in 2024, A.baumannii, a member of the multidrug resistant ESKAPE pathogens, has been listed as the most problematic, thus there is an urgent need for the rapid development of new antimicrobials. In this study, we use computational approaches to screen and identify new potential pan-inhibitor hits across the resistant strain, ATCC 17978, of the A.baumannii isoleucyl-, leucyl-, and methionyl-tRNA synthetases (IleRS, LeuRS and MetRS). A library of 70 compounds (BDA library) known to be effective against P.falciparum, M.tuberculosis, and cancer aspartate transcarbamoylase enzymes (PMID: 39937588), and its analogue library of 2868 compounds, were screened against the aaRSs of interest and their human homologs through molecular blind docking. From this, 19 selective potential pan-inhibitor hits were identified with promising binding energies across all enzymes. The binding energy differences between bacterial and human proteins was at least 0.5 suggesting potential selectivity for the bacterial enzymes over the human counterparts. The identified compounds predominantly occupied highly druggable pockets including the active site (for some IleRS-binding hits) and other pockets within essential domains such as the editing domain. These compounds are currently under further investigation through Molecular Dynamic simulations. These findings suggest potential for discovering novel hits that could serve as broad spectrum antibiotics.