Virtual Screening and Experimental Verification to Identify Potential Inhibitors of the ErmC Methyltransferase Responsible for Bacterial Resistance against Macrolide Antibiotics

Methyltransferases from the Erm family catalyze S‐adenosyl‐L‐methionine‐dependent modification of a specific adenine residue in bacterial 23S rRNA, thereby conferring resistance to clinically important macrolide, lincosamide, and streptogramin B antibiotics. Thus far, no inhibitors of these enzymes have been identified or designed that would effectively abolish the resistance in vivo. We used the crystal structure of ErmC′ methyltransferase as a target for structure‐based virtual screening of a database composed of 58 679 lead‐like compounds. Among 77 compounds selected for experimental validation (63 predicted to bind to the catalytic pocket and 14 compounds predicted to bind to the putative RNA binding site), we found several novel inhibitors that decrease the minimal inhibitory concentration of a macrolide antibiotic erythromycin toward an Escherichia coli strain that constitutively expresses ErmC′. Eight of them have IC50 values in the micromolar range. Analysis of docking models of the identified inhibitors suggests a novel strategy to develop potent and clinically useful inhibitors.