Lipoquinones, such as menaquinone (MK), are biological quinones that play pivotal roles in all living organisms. MK is the sole electron carrier in the electron transport chain of Gram-positive, Mycobacteria spp., and all anaerobically growing bacteria. The fifth enzyme in the pathway, MenE or o-succinylbenzoate CoA sythetase, catalyzes the concerted ligation of CoA to o-succinylbenzoate (OSB) via an ordered enzymatic mechanism in the presence of a divalent cation and ATP. Our previous SAR reports showed the characterization of MenE inhibitors based on acyl-AMS (5’-O-(N-acylsulfamoyl) adenosine) analogues known to inhibit adenylate-forming enzymes. We reported that OSB-AMS 1 is a tight binding inhibitor against S. aureus, Mtb, and E. coli MenE in vitro, having Kiapp values at low nM affinity. Furthermore, we also reported that 1 exists in equilibrium between an open chain keto-acid and a lactol form, either of which may be the active pharmacophore. We sought to evaluate the active pharmacophore and use this mechanistic understanding to guide future modifications to the scaffold to increase cellular activity. We developed analogues of 1 that favor either the open keto-acid or closed lactone conformation. We evaluated the mode of inhibition of 1, identify the active pharmacophore, and show cellular anti-microbial activities against pathogenic bacteria.

Menaquinone biosynthesis: An antibacterial target?

249th National Meeting (2015)

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