(213b) Heterologous Production Of The Antimalarial Drug FR900098 In E. coli And Streptomyces lividans

Antibiotics
containing P-C bonds (phosphonates and phoshinates) are a small but growing
class of compounds with important biological activities.  Phosphonates have
been shown to display a wide range of antibacterial, antiviral, pesticidal, and
anti-cancer properties.  The phosphonic acid antibiotics fosmidomycin and
FR-900098 represent a new class of antimalarial compounds that can be used to
inhibit the nonmevalonate pathway for isoprenoid biosynthesis in the
malaria-causing parasite Plasmodium falciparum.  Although no
biosynthetic pathway for fosmidomycin has been elucidated as of yet, the
biosynthetic pathway for FR-900098 has been recently cloned from Streptomyces
rubellomurinus and heterologously expressed in Streptomyces lividans. 
Here we report the creation of an E. coli strain capable of producing
the antimalarial drug FR-900098.  We present here the construction of an artificial
gene cluster that contains ten heterologous genes all under the control of individual
T7 promoters that converts cellular phosphoenoylpyruvate (PEP) and acetyl CoA
into FR-900098.  Metabolic engineering strategies aimed at optimizing gene
expression and increasing cellular PEP and acetyl CoA concentrations are also
explored.  In parallel to our work in E. coli, we also explore the
possibility of improving the production of FR-900098 in Streptomyces
lividans using metabolic engineering.