Isoprenoid Biosynthesis Pathway as a Drug Target for Bisphosphonates: Transcriptional Profile Investigation

158 p.Thesis (Ph.D.)--University of Illinois at Urbana-Champaign, 2007.Bisphosphonates are known as potent inhibitors of the enzyme farnesyl diphosphate synthase (FPPS) and are clinically used to treat bone related disorders such as osteoporosis and bone cancer. Here we describe the development, testing and study of the mechanism of action of novel bisphosphonates as anti-bacterial and anti-cancer agents. We identified a FPPS bisphosphonate inhibitor which in combination with the phosphonate drug fosmidomycin exerted a potent synergistic effect in Escherichia coli. Additionally, we designed novel groups of bisphosphonates which are ∼10-1000 fold more potent against tumor cell lines than conventional bisphosphonates due to their ability to inhibit more than one enzyme in the mevalonate pathway.U of I OnlyRestricted to the U of I community idenfinitely during batch ingest of legacy ETD