Mechanistic studies of the enoyl‐ACP reductase from Yersinia pestis and its inhibition by diaryl ether compounds

Abstract

Yersinia pestis is a gram‐negative bacterium which causes bubonic and pneumonic plague. Due to the microbe's ability to spread rapidly and cause high mortality, the Centers for Disease Control and Prevention (CDC) have classified this organism as a Category A pathogen as it can be easily utilized as a biological weapon. Currently, streptomycin or gentamicin is used for the treatment of this disease. However, neither of the drugs can be orally administered, thus limiting their potential usefulness. The bacterial fatty acid synthesis (FAS‐II) pathway is essential for bacterial viability and it has also been validated as an attractive target for the discovery of novel antibacterials. We have cloned, over‐expressed and purified FabV, the FAS‐II enoyl‐ACP reductase from Yersinia pestis (ypFabV). In vitro kinetic experiments demonstrated that the recombinant enzyme can efficiently catalyze the reduction of the synthetic substrate using Trans‐2‐dodecenoyl‐CoA (DD‐CoA) as the substrate and NADH as the cofactor. Structural activity relationship (SAR) studies have lead us to the identification of a series of diaryl ether inhibitors with Ki values as low as 0.50 μM and MIC values as low as 0.5 μg/ml.