# Echinocandins: structural diversity, biosynthesis, and development of antimycotics

## TL;DR

This review discusses the biosynthesis and development of echinocandins, a class of antifungal drugs, highlighting their complex structure and recent advances in genetic engineering.

## Contribution

The paper provides a detailed overview of echinocandin biosynthesis and recent genetic methods for engineering their production.

## Key findings

- Echinocandins are complex lipopeptides with numerous hydroxylated non-proteinogenic amino acids.
- Recent identification of biosynthetic gene clusters has enabled molecular-level engineering of echinocandin production.
- Structure−activity relationships are crucial for optimizing drug properties like solubility and stability.

## Abstract

Echinocandins are a clinically important class of non-ribosomal antifungal lipopeptides produced by filamentous fungi. Due to their complex structure, which is characterized by numerous hydroxylated non-proteinogenic amino acids, echinocandin antifungal agents are manufactured semisynthetically. The development of optimized echinocandin structures is therefore closely connected to their biosynthesis. Enormous efforts in industrial research and development including fermentation, classical mutagenesis, isotope labeling, and chemical synthesis eventually led to the development of the active ingredients caspofungin, micafungin, and anidulafungin, which are now used as first-line treatments against invasive mycosis. In the last years, echinocandin biosynthetic gene clusters have been identified, which allowed for the elucidation but also engineering of echinocandin biosynthesis on the molecular level. After a short description of the history of echinocandin research, this review provides an overview of the current knowledge of echinocandin biosynthesis with a special focus of the diverse structural elements, their biosynthetic background, and structure−activity relationships.

• Complex and highly oxidized lipopeptides produced by fungi.

• Crucial in the design of drugs: side chain, solubility, and hydrolytic stability.

• Genetic methods for engineering biosynthesis have recently become available.

The online version contains supplementary material available at 10.1007/s00253-020-11022-y.