Isoprenoid Metabolism as a Therapeutic Target in Gram-Negative Pathogens

Andrew      J. Wiemer; Chia-Hung      Christine Hsiao; David      F. Wiemer

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.

Keywords: Isoprene, terpene, Escherichia coli, geranylgeranyl diphosphate synthase, bisphosphonate, farnesyl diphosphate, farnesyl pyrophosphate, Gram-negative, mevalonate pathway, MEP pathway, Enterobacteria, facultative anaerobes, isoprenoid bio-synthetic pathway inhibitors, Non-Mevalonate Pathway, Isopentenyl diphosphate (IPP), HMG-CoA, HMG-CoA reductase, statin drugs, hypercholes-terolemia, diphos-phomevalonate, me-valonate kinase, phosphomevalonate kinase, 1-deoxy-D-xylulose-5-phosphate (DOXP), DOXP reductoi-somerase, fosmidomycin, Dxr, Dxr inhibitors, glycerol 3-phosphate transporter, IspD, 4-diphosphocytidyl-2C-methyl-D-erythritol kinase, pro-teobacteria, Mesorhizobium loti, IspDF, IspF, HMBPP reductase, C15 isoprenoid farnesyl diphosphate, phosphoantigens, human gamma delta T cells, FPP synthase, hy-drophobic bisphosphonates, octaprenyl diphosphate synthase, ubiquinone, menaquinone, QUINONE SYNTHESIS, Prenylated Quinones, disulfide-bond formation, Long-Chain Trans-Prenyl Synthase, Trans-Prenyl Transferase, hydroxybenzoate polyprenyl transferase, methyl transferases, ispB knockout strain, non-hydroxylation reactions enzymes, chorismate, isochorismate synthase, demeth-ylmenaquinone, menaquinone bio-synthesis, derivatives of hypoxanthine, polyprenyl synthase IspB, octaprenyl diphos-phate, human prenyltransferases, farnesyl analogs, hydroxyfarnesyl phosphonic acid, UbiA inhibition, POLYPRENOLS, CELL WALL BIOSYN-THESIS, N-acetyl-glucosamine, N-acetylmuramic acid, isoprenyl transferases, MraY and MurG enzymes, UPP phosphatase activity, undecaprenyl phosphate, phospho-MurNAc-pentapeptide translocase, peptidoglycan glycosyl transferase, uridine diphosphate, Bacitracin, polyprenyl diphosphate, geranylgeranyl diphosphate, polyisoprenoids, farnesyl transferase, geranyl-geranyl transferase, squalene synthase, bisphosphonate moiety, Core Isoprene Synthesis, Quinone Metabolism, Polyprenol Metabolism