Assembly of aryl-capped siderophores by modular peptide synthetases and polyketide synthases

Bacterial siderophores assist pathogens in iron acquisition inside their ho sts. They are often essential for achieving a successful infection, and the ir biosynthesis represents an attractive antibiotic target. Recently, sever al siderophore biosynthetic loci have been identified, and in vitro studies have advanced our knowledge of the biosynthesis of aryl-capped peptide and peptide-polyketide siderophores from Mycobacterium spp., Pseudomonas spp., Yersinia spp. and other bacteria. These studies also provided insights int o the assembly of related siderophores and many secondary metabolites of me dical relevance. Assembly of aryl-capped peptide and peptide-polyketide sid erophores involves non-ribosomal peptide synthetase, polyketide synthase an d non-ribosomal-peptide polyketide hybrid subunits. Analysis of these subun its suggests that their domains and modules are functionally and structural ly independent. It appears that nature has selected a set of functional dom ains and modules that can be rearranged in different order and combinations to biosynthesize different products. Although much remains to be learned a bout modular synthetases and synthases, it is already possible to conceive strategies to engineer these enzymes to generate novel products.