Discovery and characterization of bioactive phosphonic acid biosynthetic pathways

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Phosphonic acids are characterized by stable carbon-phosphorus bonds. A number of naturally produced phosphonates have been discovered which possess antibiotic activity. Fosmidomycin, a phosphonate produced by Streptomyces lavendulae, inhibits the nonmevalonate pathway of isoprenoid biosynthesis at an early stage, blocking the enzyme deoxyxylulose phosphate reductoisomerase (DXR). This pathway has been detected in the Malaria causing parasite Plasmodium falciparum, and fosmidomycin has been demonstrated to be active against this parasite. The aim of this project is to investigate the biosynthetic pathway of fosmidomycin and to elucidate the molecular basis of resistance against this compound. The biosynthetic gene cluster of this secondary metabolite has been cloned and sequenced. The identified open reading frames suggest that the fosmidomycin pathway differs from the recently elucidated pathway of the structurally similar compound FR900098. Knock-out mutants will be generated and analyzed for their production profile. Furthermore, enzymatic reactions will be tested in vitro to prove the proposed pathway and to understand the biochemistry of enzymes acting on C-P compounds. The elucidation of the pathway will help develop novel phosphonate lead compounds via combinatorial biosynthesis.