Biosynthetic Pathways and Total Synthesis of Antibiotics

Antibiotics have long relied on two complementary approaches: the exploitation of natural biosynthetic pathways and the de novo or semisynthetic construction of complex molecular scaffolds. Biosynthetic pathways harness multienzyme assemblies encoded in microbial genomes to assemble small‐molecule antibiotics via iterative condensation, oxidation and cyclisation steps. Advances in genome mining and heterologous expression have revealed new gene clusters and atypical enzymatic functions, enabling access to novel structures and facilitating pathway engineering for enhanced yields or altered functionalities. In parallel, total synthesis efforts tackle the formidable stereochemical and macrocyclic architectures of natural antibiotics, providing unambiguous structural proof and enabling analogue design. Chemical strategies such as biomimetic macrocyclisation, site‐selective catalysis and convergent fragment coupling have yielded first syntheses of intricate polyketides, glycopeptides and lipopeptides. The interplay between enzymology and organic chemistry drives a virtuous cycle: insights into biosynthetic mechanisms inform synthetic routes, while synthetic analogues serve as probes of enzyme specificity and resistance profiles. Together, these endeavours underpin the discovery of new leads, allow rapid generation of structure–activity relationship data and offer routes to overcome emerging resistance threats on a global scale.

Research from Nature Portfolio

Recent studies have uncovered extraordinary multifunctionality within biosynthetic enzymes. Investigation of a monoamine oxidase‐related catalyst in lankacidin assembly revealed a single polypeptide that orchestrates both amide oxidation and intramolecular Mannich macrocyclisation. Structural analysis demonstrated unique domain movements and dimer interfaces that underpin this dual reactivity, suggesting strategies for engineering bespoke cyclases in synthetic biology. A separate line of work has exploited cryo-electron microscopy to guide site-selective chemical modifications of a complex glycosylated antibiotic scaffold. Strategic esterifications and selective glycosidic cleavages produced novel analogues with broadened spectrum and improved pharmacokinetics, illustrating how structural insight can drive semisynthetic diversification and counteract resistance in clinically important pathogens.

Biosynthetic Pathways and Total Synthesis of Antibiotics publication trend

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

Technical terms

Biosynthetic pathway: A series of enzyme-mediated reactions in microbes that convert simple precursors into complex natural products.

Total synthesis: The complete chemical construction of a complex molecule from simple starting materials without use of the native biological pathway.

Macrocyclisation: The intramolecular formation of a large ring, often crucial for the biological activity of many natural antibiotics.

Polyketide: A class of natural products built by the stepwise condensation of small acyl units, frequently forming macrolide antibiotics.

Semisynthesis: A hybrid approach in which a natural product is chemically modified to generate derivatives with improved properties.

References

1. Biomimetic Synthesis of Chejuenolides A–C by a Cryptic Lactone-Based Macrocyclization: Stereochemical Implications in Biosynthesis. ACS Central Science (2023).
2. Insights into a dual function amide oxidase/macrocyclase from lankacidin biosynthesis. Nature Communications (2018).
3. Novel fidaxomicin antibiotics through site-selective catalysis. Communications Chemistry (2021).
4. Total Synthesis of Kibdelomycin. Angewandte Chemie (2022).
5. Actinomycetes: A Never-Ending Source of Bioactive Compounds—An Overview on Antibiotics Production. Antibiotics (2021).