(439a) Biosynthesis of Phosphonates for the Treatment of Malaria

Antibiotics containing C-P bonds, phosphonates and phosphinates, are a potent group of bioactive compounds. The phosphonic acids fosmidomycin and FR-900098 are novel chemotherapeutic agents for the treatment of malaria and have been shown to be effective in humans and other animals. These compounds inhibit 1-deoxy-D-xylulose 5-phosphate (DXP) reductoisomerase, the first committed enzyme in the nonmevalonate pathway for isoprenoid biosynthesis in many bacteria as well as Plasmodium falciparum, the parasite responsible for the most virulent form of the disease. The biosynthetic cluster for FR-900098 has recently been cloned from the native Streptomyces rubellomurinus and heterologously expressed in Streptomyces lividans and E. coli.

We have used the genetic machinery encoded in the FR-900098 biosynthetic cluster as building blocks toward the development of more potent inhibitors of the nonmevalonate pathway. In particular, a route for the production of another phosphonate antibiotic, FR-33289, was revealed in the cluster. Also, combinatorial biosynthesis was performed by introducing elements of other phosphonate biosynthetic pathways in hopes of increasing the bioefficacy and bioavailability of the final products. Here we also present efforts towards pathway engineering in the heterologous E. coli host and fermentation studies for the improvement in production of these antimalarial drugs towards more industrially viable levels.