Biosynthetic Pathways of Peptide Antibiotics

Peptide antibiotics encompass a structurally diverse array of compounds produced by microorganisms through dedicated enzymatic assembly lines. Broadly, they arise via two principal routes: nonribosomal peptide synthetases (NRPS) that operate as modular mega‐enzymes to incorporate proteinogenic and non‐proteinogenic amino acids, and ribosomally synthesised and post-translationally modified peptides (RiPPs) that rely on precursor peptides and tailoring enzymes. These pathways are typically encoded within biosynthetic gene clusters (BGCs) that coordinate assembly, tailoring (for example glycosylation, halogenation, acylation) and secretion. Structural diversity is generated through selective domain organisation, substrate promiscuity and iterative chain release by thioesterase domains. Regulatory circuits respond to environmental cues and self-resistance mechanisms ensure producer survival. Ongoing research has emphasised the evolutionary plasticity of assembly machinery, revealing how natural selection and horizontal gene transfer shape novel scaffolds. Understanding these processes underpins efforts in synthetic biology to refactor pathways, optimise yields and mine cryptic clusters, with the ultimate goal of expanding the antibiotic arsenal against resistant pathogens.

Research from Nature Portfolio

Recent studies have reconstructed ancestral lipid II-targeting glycopeptide scaffolds by combining computational prediction of paleoenzyme architecture with synthetic biology, thereby reviving early nonribosomal pathways and uncovering evolutionary snapshots of domain selection. This work revealed how successive modifications in NRPS modules have refined modern glycopeptides and laid a blueprint for engineering novel analogues. In parallel, a heterologous expression platform has been developed that integrates specialised biosynthetic blocks, regulators and resistance elements into a chassis strain, achieving a marked increase in glycopeptide titres, discovery of cryptic nonapeptides and overproduction of clinically relevant compounds. These advances demonstrate the power of pathway modularisation and chassis design for both production enhancement and natural product discovery.

Biosynthetic Pathways of Peptide Antibiotics publication trend

The graph below shows the total number of articles in biosynthetic pathways of peptide antibiotics across all publications each year (not limited to Nature Index journals).

Technical terms

Nonribosomal peptide synthetase (NRPS): A modular enzyme complex that assembles peptide antibiotics independently of the ribosome, often incorporating unusual amino acids and tailoring domains.

Biosynthetic gene cluster (BGC): A contiguous set of genes encoding enzymes, regulators and transporters required for the synthesis of a secondary metabolite.

Heterologous expression: The production of a biosynthetic pathway in a non-native host organism to facilitate pathway characterisation, yield improvement or novel compound discovery.

Acylase: An enzyme that removes, transfers or modifies acyl side chains on peptides, critical for generating lipidated or de-lipidated antibiotic forms.

Glycopeptide antibiotic: A class of peptide antibiotics characterised by sugar decorations and nonribosomal assembly, which target bacterial cell-wall precursors such as lipid II.

References

1. Resurrecting ancestral antibiotics: unveiling the origins of modern lipid II targeting glycopeptides. Nature Communications (2023).
2. GPAHex-A synthetic biology platform for Type IV–V glycopeptide antibiotic production and discovery. Nature Communications (2020).
3. A Hadal Streptomyces-Derived Echinocandin Acylase Discovered through the Prioritization of Protein Families. Marine Drugs (2024).
4. Rational construction of a high-quality and high-efficiency biosynthetic system and fermentation optimization for A82846B based on combinatorial strategies in Amycolatopsis orientalis. Microbial Cell Factories (2024).