Isoprenoid metabolism as a therapeutic target in gram-negative pathogens

Abstract

Gram-negative Enterobacteria include a variety of human pathogens, perhaps most notably E. coli, Salmonella, Shigella, Yersinia, and Proteus. While there are treatment options for the diseases caused by these organisms, multi-drug resistance is often a problem and development of novel antibiotics has lagged over recent years. In humans, the isoprenoid biosynthetic pathway has become a subject of intense research for therapeutic modulation of human enzymes in diseases including hypercholesterolemia, osteoporosis, and cancer. In bacteria, isoprenoid metabolism is arguably just as important, giving rise to components that are essential for electron transport and cell wall biosynthesis. Blocking these biosynthetic processes, either with the antibiotic fosmidomycin or by gene knockout strategies, has demonstrated the necessity of isoprenoid biosynthesis for bacterial growth. In this review, current knowledge of the biochemical pathways involved in farnesyl diphosphate metabolism in Enterobacteria, efforts to develop inhibitors of the involved enzymes, and insights from inhibitors of human isoprenoid metabolism that may be relevant for future studies of antibiotics that target these key enzymes, are described.