The first successful production of the antibiotic erythromycin A, and two variations, with E.Coli as the source has been reported by researchers at Tufts University School of Engineering.
The work, published in the November 24, 2010, issue of Chemistry and Biology,
offers a more cost-effective way to make both erythromycin A and new drugs that will combat the growing incidence of antibiotic resistant pathogens. Equally important, the E. coli
production platform offers numerous next-generation engineering opportunities for other natural products with complex biosynthetic pathways.
"We have now established E. coli
as a viable option for making erythromycin A and as a platform for the directed production of erythromycin analogs. Our ability to fully manipulate erythromycin A's biosynthetic pathway to expand molecular diversity and antibiotic activity help sets a precedent for producing other similarly complex and medicinally relevant natural products," said lead researcher Blaine Pfeifer, Ph.D., assistant professor of chemical and biological engineering at Tufts.
Erythromycin A is a potent weapon in the treatment of bacterial infections. The bacterium Saccharopolyspora erythraea, which is found in the soil, naturally produces several variants of erythromycin. Erythromycin A is the most common and most biologically active.
Because of the challenges associated with engineering Saccharopolyspora erythraea, researchers have hoped to achieve the complete production of erythromycin A using E. coli
. More than 20 enzymes must work in concert to create the erythromycin A molecule. This genetic and biochemical complexity makes synthesis notoriously hard. Previous research had reported manufacture of erythromycin A intermediates in E. coli
but not the final product.
"To transfer and reconstitute these biosynthetic pathways is very difficult. In fact, erythromycin A poses nearly every challenge that must be addressed in the quest for complex heterologous biosynthesis of natural products," Pfeifer said.