Biosynthesis and biosynthetic engineering of calcium-dependent lipopeptide antibiotics

Biosynthetic engineering involves the reprogramming of genes that are involved in the biosynthesis of natural products to generate new "non-natural" products, which might otherwise not exist in nature. Potentially this approach can be used to provide large numbers of secondary metabolite variants, with altered biological activities, many of which are too complex for effective total synthesis. Recently we have been investigating the biosynthesis of the calcium-dependent antibiotics (CDAs) which are members of the therapeutically relevant class of acidic lipopeptide antibiotics. CDAs are assembled by nonribosomal peptide synthetase (NRPS) enzymes. These large modular assembly-line enzymes process intermediates that are covalently tethered to peptidyl carrier protein (PCP) domain bonds, which makes them particularly amenable to reprogramming. The CDA producer, Streptomyces coelicolor, is also a genetically tractable model organism which makes CDAs an ideal template for biosynthetic engineering. To this end, we have elucidated many of the key steps in CDA biosynthesis and utilized this information to develop methods that have enabled the engineered biosynthesis of a wide range of CDA-type lipopeptides.