Gram-negative bacteria have become increasingly resistant to known antibiotic treatments, necessitating the discovery of new treatment mechanisms. LpxC catalyzes the first committed step in biosynthesis of lipid A, a component of the outer membranes of Gram-negative bacteria and is, therefore, a promising target for inhibition. Using known characteristics of the active site, potential inhibitors were designed to optimally bind and inhibit LpxC. Non-nucleoside analogues of the natural substrate were chosen to improve interaction with the zinc ion and hydrophobic region. Ligand-protein interaction energies of these analogues were calculated <i>in silico</i> using a DFT/PM6 ONIOM model. Compounds with the most favorable interactions were synthesized and characterized with the intent to study their enzymatic activity.

Design and synthesis of non-nucleoside as potential inhibitors of LpxC

255th National Meeting (2018)

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