Control of fluxes towards antibiotics and the role of primary metabolism in production of antibiotics.

Yield improvements in antibiotic-producing strains have classically been obtained through random mutagenesis and screening. An attractive alternative to this strategy is the rational design of producer strains via metabolic engineering, an approach that offers the possibility to increase yields while avoiding the problems of by-product formation and altered morphological properties, which frequently arise in mutagenized strains. An important aspect in the design of strains with improved yields by metabolic engineering is the identification of rate-controlling enzymatic reactions in the metabolic network. Here we describe and discuss available methods for identification of these steps, both in antibiotic biosynthesis pathways and in the primary metabolism, which serves as the supplier of precursors and cofactors for the secondary metabolism. Finally, the importance of precursor and cofactor supply from primary metabolism in the biosynthesis of different types of antibiotics is discussed and recent developments in metabolic engineering towards increased product yields in antibiotic producing strains are reviewed.