A Hadal Streptomyces-Derived Echinocandin Acylase Discovered through the Prioritization of Protein Families

TL;DR

Scientists discovered a new enzyme from deep-sea bacteria that can modify antifungal drugs, potentially improving their safety and effectiveness.

Contribution

The discovery of the first echinocandin E acylase from a hadal Streptomyces species using protein family prioritization.

Findings

Echinocandin E acylase (ECEA) was identified from a deep-sea Streptomyces sp. SY1965 isolate.

The enzyme efficiently cleaves the acyl side chain of echinocandin E, aiding drug development.

The study highlights the potential of hadal ecosystems for discovering functional molecules.

Abstract

Naturally occurring echinocandin B and FR901379 are potent antifungal lipopeptides featuring a cyclic hexapeptide nucleus and a fatty acid side chain. They are the parent compounds of echinocandin drugs for the treatment of severe fungal infections caused by the Candida and Aspergilla species. To minimize hemolytic toxicity, the native fatty acid side chains in these drug molecules are replaced with designer acyl side chains. The deacylation of the N-acyl side chain is, therefore, a crucial step for the development and manufacturing of echinocandin-type antibiotics. Echinocandin E (ECE) is a novel echinocandin congener with enhanced stability generated via the engineering of the biosynthetic machinery of echinocandin B (ECB). In the present study, we report the discovery of the first echinocandin E acylase (ECEA) using the enzyme similarity tool (EST) for enzymatic function mining across protein families. ECEA is derived from Streptomyces sp. SY1965 isolated from a sediment collected from the Mariana Trench. It was cloned and heterologously expressed in S. lividans TK24. The resultant TKecea66 strain showed efficient cleavage activity of the acyl side chain of ECE, showing promising applications in the development of novel echinocandin-type therapeutics. Our results also provide a showcase for harnessing the essentially untapped biodiversity from the hadal ecosystems for the discovery of functional molecules.

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