Accessorizing natural products: Adding to nature's toolbox

Abstract

Over a century of effort of synthetic medicinal chemistry has not replaced natural products as essential components of our therapeutic arsenal. In fact, for some classes of drugs, such as the antibiotics, natural products and their semisynthetic derivatives dominate. Natural products can also have significant roles in pathology, e.g., by contributing to virulence during infection. The majority of natural products produced by microorganisms, marine organisms, and plants use one or a combination of three scaffold assembly plans: ( i ) nonribosomal peptide biosynthesis, ( ii ) polyketide assembly, and ( iii ) alkaloid biosynthesis. Whereas these scaffolds provide the first level of structural diversity, additional complexity and structural and functional expansion occur through a molecular toolkit of accessorizing proteins that are increasingly recognized as vital to our understanding and manipulation of new natural products and as potential targets for therapeutic agents (Fig. 1). In this issue of PNAS, Fischbach et al . (1) expand this toolkit with their characterization of IroB, a C -glycosyltransferase that modifies an iron-chelating siderophore that is a potential virulence factor in Salmonella . Fig. 1. Diversity of natural products by means of biocombinatorial chemistry. Initially, biochemical modification of a scaffold results in a small number of structurally distinct compounds (C1, C2, and C3), followed by the production of more complex and unique compounds (C1a, C1b, C1c, etc.). Microorganisms produce a plethora of natural products for diverse uses. These applications include protection from competing strains (2), chemical messengers for cell-cell communication (3), agents to facilitate colonization of a host (4), and gene regulation (5). The proven track record of natural products and their attributes as modulators of biological activity have made …