Nature Builds Macrocycles and Heterocycles into Its Antimicrobial Frameworks: Deciphering Biosynthetic Strategy

Natural products with anti-infective activity are largely of polyketide or peptide origin. The nascent scaffolds typically undergo further enzymatic morphing to produce mature active structures. Two kinds of common constraints during maturation of immature scaffolds to active end point metabolites are macrocyclizations and hetrocyclizations. Each builds compact architectures characteristic of many high affinity, specific ligands for therapeutic targets. The chemical logic and enzymatic machinery for macrolactone and macrolactam formations are analyzed for antibiotics such as erythromycins, daptomycin, polymyxins, and vancomycin. In parallel, biosynthetic enzymes build small ring heterocycles, including epoxides, β-lactams, and β-lactones, cyclic ethers such as tetrahydrofurans and tetrahydropyrans, thiazoles, and oxazoles, as well as some seven- and eight-member heterocyclic rings. Combinations of fused heterocyclic scaffolds and heterocycles embedded in macrocycles reveal nature's chemical logic for building active molecular frameworks in short efficient pathways.