In silico and in vitro Identification of Compounds with Dual Pharmacological Activity against Metionyl-tRNA Synthetase and Isoleucyl-tRNA Synthetase of Staphylococcus aureus

The spread of drug-resistant Staphylococcus aureus (S. aureus) in hospitals and communities poses a serious medical threat. This study aimed to identify aminoacyl-tRNA synthetase inhibitors with antimicrobial activity against S. aureus. In silico structure-based drug screening using docking and molecular dynamics simulations (MDS) was performed targeting S. aureus metionyl-tRNA synthetase (saMetRS). Ten candidate compounds were selected by screening a compound 3D structure library with 154,118 compounds. One compound (Compound 9) showed a strong inhibitory effect in growth inhibition studies using Staphylococcus epidermidis. From the experiments verifying the dose-dependent effect, the IC50 value of Compound 9 was determined to be 3.74 mu M. MDSs predicted that Compound 9 exhibits inhibitory activity against saMetRS and S. aureus isoleucyl-tRNA synthetase, which belongs to the same subclass Ia. Compound 9 with its polypharmacological activity is not susceptible to drug resistance and is expected to have enhanced antimicrobial efficacy.