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

Area of Science:

• Biochemistry
• Natural Product Chemistry
• Medicinal Chemistry

Background:

• Anti-infective natural products are predominantly polyketides or peptides.
• Immature natural product scaffolds undergo enzymatic modifications to yield active compounds.
• Macrocyclization and heterocyclization are key enzymatic processes in natural product biosynthesis.

Purpose of the Study:

• To analyze the chemical logic and enzymatic machinery behind macrocyclization and heterocyclization in natural product maturation.
• To explore how these processes contribute to the formation of compact, high-affinity molecular architectures.
• To understand nature's strategies for efficiently synthesizing complex anti-infective agents.

Main Methods:

• Analysis of biosynthetic pathways for antibiotics like erythromycins, daptomycin, polymyxins, and vancomycin.
• Examination of enzymatic mechanisms for macrolactone and macrolactam formation.
• Review of enzymes involved in synthesizing various small heterocyclic rings (epoxides, beta-lactams, etc.).

Main Results:

• Macrolactonization and macrolactamization are crucial for forming cyclic structures in antibiotics.
• Biosynthetic enzymes efficiently construct diverse small heterocycles, including epoxides, beta-lactams, and cyclic ethers.
• Combinations of fused heterocycles and macrocycles are prevalent in nature's molecular designs.

Conclusions:

• Nature employs elegant enzymatic strategies for macrocyclization and heterocyclization to produce potent anti-infectives.
• These processes are vital for generating the complex, compact structures characteristic of high-affinity ligands.
• Understanding these biosynthetic pathways offers insights into designing novel therapeutic agents.