Rational Design Of Mene Inhibitors: The Design And Development Of Novel Antibiotics

Abstract

In order for our society to avoid entering a post-antibiotic era, we need new antibiotics that function through pathways and mechanisms previously untargeted by our current regimen of antibiotics. One such pathway is that of menaquinone biosynthesis. Menaquinone is responsible for electron transport in bacterial respiration and is required for the growth and proliferation of many virulent bacteria such as Mycobacterium tuberculosis. Herein, we report efforts in developing a new class of antibiotics, which aim to inhibit menaquinone biosynthesis through targeting of a key enzyme in the biosynthetic pathway, MenE. MenE is an acyl-CoA ligase, which converts osuccinyl benzoate (OSB) to OSB-CoA via an OSB-AMP intermediate. Using 5?-O-(N-acylsulfamoyl) adenosine (acyl-AMS) analogues of the cognate acyl- AMP intermediate, we can effectively inhibit MenE in biochemical assays, but these inhibitors show poor cellular activity as well as unfavorable physicochemical and pharmacological properties, impeding the progression of this inhibitor platform. Utilizing crystal and docking structures, exploration of the structure-activity relationships of the scaffold, and the unique ketoacid/ lactol equilibrium of OSB-AMS, we are developing a series of second and third generation OSB-AMS analogues designed to increase cellular activity and progress this inhibitor class.