Cephalosporin Biosynthesis in Filamentous Fungi

Cephalosporins are a class of β-lactam antibiotics renowned for their broad-spectrum activity and clinical importance. In filamentous fungi, notably Acremonium chrysogenum, biosynthesis begins with the non-ribosomal assembly of the tripeptide δ-(l-α-aminoadipyl)-l-cysteinyl-d-valine (ACV) by ACV synthetase. ACV is cyclised to penicillin N by isopenicillin N synthase, then converted via oxidative ring expansion and hydroxylation to deacetoxycephalosporin C and deacetylcephalosporin C by multifunctional expandase/hydroxylase enzymes. Finally, an acetyltransferase utilises acetyl coenzyme A to yield cephalosporin C (CPC). Genes encoding these enzymes cluster in a biosynthetic gene cluster (BGC) that is co-regulated by pathway-specific transcription factors and global regulators responsive to environmental cues. Industrial strain improvement, through classical mutagenesis or targeted metabolic engineering, has enhanced precursor supply, alleviated oxidative stress, and remodelled primary metabolism to elevate CPC titres. Process parameters such as dissolved oxygen, pH and nutrient feed also critically influence enzyme activity, ATP availability and hyphal morphology, all of which underpin efficient antibiotic production.

Research from Nature Portfolio

No recent Nature Portfolio content available.

Cephalosporin Biosynthesis in Filamentous Fungi publication trend

The graph below shows the total number of articles in cephalosporin biosynthesis in filamentous fungi across all publications each year (not limited to Nature Index journals).

Technical terms

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

Cephalosporin C (CPC): The native product of the fungal biosynthetic pathway, serving as a precursor for semisynthetic cephalosporin antibiotics.

Non-ribosomal peptide synthetase (NRPS): A large, multi-domain enzyme that assembles peptide intermediates independent of the ribosome.

Oxidative ring expansion: A biochemical transformation that converts the five-membered penam nucleus into a six-membered cephem core via oxygen-dependent enzymatic steps.

Acetyl coenzyme A: A central metabolite that donates acetyl groups in the final acetylation step of cephalosporin C formation.

References

1. Effect of catalase on CPC production during fermentation of Acremonium chrysogenum. Bioresources and Bioprocessing (2025).
2. Undefined xylose media extracted from biorefinery waste for enhanced and eco‐friendly production of cephalosporin C by Acremonium chrysogenum M35. GCB Bioenergy (2023).
3. Spermidine and 1,3-Diaminopropane Have Opposite Effects on the Final Stage of Cephalosporin C Biosynthesis in High-Yielding Acremonium chrysogenum Strain. International Journal of Molecular Sciences (2022).
4. Fungal BGCs for Production of Secondary Metabolites: Main Types, Central Roles in Strain Improvement, and Regulation According to the Piano Principle. International Journal of Molecular Sciences (2023).
5. Industrial Production of Antibiotics in Fungi: Current State, Deciphering the Molecular Basis of Classical Strain Improvement and Increasing the Production of High-Yielding Strains by the Addition of Low-Molecular Weight Inducers. Fermentation (2023).