  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.
