Novel macrolides through genetic engineering

Abstract

Erythromycin, a complex polyketide antibiotic belonging to the macrolide class, is produced as a natural product by the bacterium Saccharopolyspora erythraea. The genes encoding the enzymes responsible for the synthesis of the antibiotic have been cloned and sequenced, revealing that the polyketide backbone of the molecule in produced by a polyketide synthase (PKS) composed of multifunctional proteins that contain discrete functional domains for each step of synthesis. Genetic manipulation of the PKS-encoding genes can result in predictable changes in the structure of the polyketide component of erythromycin, many of which are not easily achievable through standard chemical derivatization or synthesis. Many of the changes can be combined to lead to the further generation of navel structures. Whereas genetic engineering of the erythromycin structure has been practiced for a number of years, the re cent and continuing discoveries of modular PKSs for the synthesis of many other important complex polyketides has raised the possibility of generating novel structures in these molecules by genetic manipulation, as well.