Pharmacophore and ligand-guided screening of antibacterial leads targeting antibiotic resistance factor in Gram-negative bacteria

Abstract

Pathogenic Gram-negative bacteria have developed resistance to antibiotics due to their ability in creating an envelope on the outer layer of lipooligosaccharides (LOS). The cationic phosphoethanolamine (PEA) decoration of LOS lipid A is regulated by lipid A-PEA transferase (EptA) which may serve as a prominent target for developing new antibiotics. The structural characterization of Neisserial EptA has provided a structural basis to its catalytic mechanisms and ligand recognition that are crucial for inhibitor development. In this study, a combination of pharmacophore- and ligand-based approach has been employed to explore novel potent EptA inhibitors among millions of commercially-available compounds and approved drugs. A total of 8166 hit molecules obtained from ZincPharmer pharmacophore-based screening and PubMed ligand similarity search were further examined through individual two-step semi-flexible docking simulation performed in MOE. Best hits were therefore selected based on their docking score and consensus of the two docking validations. Free energy of binding calculation suggests that the best 20 consensus compounds have a stronger binding affinity than EptA natural substrate PEA. Further interaction analyses of selected eight ligands demonstrate that these ligands have overall more effective interactions with catalytically-essential residues and metal cofactors of EptA. Selected hits can be further analyzed in vitro and examined through a pre-clinical trial. This study provides an insight into drug repurposing which may serve as an initial step to develop novel potent EptA inhibitors to combat the virulence of multi-drug resistant Gram-negative bacteria.