Coordination Chemistry Based Approach to Lipophilic Inhibitors of 1-Deoxy-d-xylulose-5-phosphate Reductoisomerase

Abstract

1-Deoxy-d-xylulose-5-phosphate reductoisomerase (DXR) in the non-mevalonate pathway found in most bacteria is a validated anti-infective drug target. Fosmidomycin, a potent DXR inhibitor, is active against Gram-negative bacteria. A coordination chemistry and structure based approach was used to discover a novel, lipophilic DXR inhibitor with an IC50 of 1.4 μM. It exhibited a broad spectrum of activity against Gram-negative and -positive bacteria with minimal inhibition concentrations of 20−100 μM (or 3.7−19 μg/mL).