A ligand-based approach for enhancing the pharmacokinetic profile of highly charged antibacterial agents

Abstract

Glutamate racemase catalyses the interconversion of l-glutamate and d-glutamate making available d-glutamate which is essential for peptidoglycan biosynthesis. Inhibitors of this enzyme have exhibited antibacterial activity with the d-glutamate-analogues group of inhibitors being the most significant as it is the only group that has demonstrated efficacy in a murine thigh Streptococcus pneumoniae infection model. This group of inhibitors, however, showed a narrow antibacterial spectrum that could be due to poor lipophilicity and permeability properties. Here, we have adopted a computational ligand-based drug design approach to enhance the lipophilicity and, hence, the antibacterial spectrum of this group of inhibitors. By limiting the charged groups on our pharmacophore model and identifying key interactions for glutamate racemase binding and inhibition, we have successfully searched a compound database for compounds with both antibacterial activity and increased lipophilicity. However, our compounds appear less potent, likely due to decreased specificity. We also demonstrate that permeability and lipophilicity alone are not responsible for the narrow antibacterial spectrum observed in the d-glutamate analogue inhibitors.