Echinocandins: structural diversity, biosynthesis, and development of antimycotics
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MINI-REVIEW
Echinocandins: structural diversity, biosynthesis, and development of antimycotics Wolfgang Hüttel 1 Received: 28 September 2020 / Revised: 6 November 2020 / Accepted: 12 November 2020 # The Author(s) 2020
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. Key points • 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. Keywords Bioactivity . Filamentous fungi . Hydroxylases . Metabolic diversity . Non-ribosomal peptide biosynthesis . Secondary metabolism
Introduction Echinocandins are cyclic non-ribosomal hexapeptides equipped with a lipophilic side chain. They are produced by filamentous fungi (Ascomycota) of the classes Leotiomycetes (mostly Helotiales) and Eurotiomycetes (Aspergillaceae). Thus, echinocandin biosynthesis is widespread albeit not frequent among Ascomycetes (Yue et al. 2015). Due to their strong inhibitory effect on 1,3-βD-glucan synthase, an enzyme required for cell wall
* Wolfgang Hüttel [email protected] 1
Institute of Pharmaceutical Sciences, University of Freiburg, Albertstr. 25, 79106 Freiburg, Germany
biosynthesis in fungi, echinocandins are potent antifungal compounds. The semisynthetic derivatives caspofungin (Cancidas®), micafungin (Mycamine®), and anidulafungin (Eraxis®) are first-line antimycotics for the treatment of invasive mycosis (Denning 2002; Patil and Majumdar 2017). Echinocandins have a distinctive cyclic lipopeptide structure assembled by a nonribosomal peptide synthase (NRPS) (cf. Fig. 2). Six amino acids, up to five of which are non-proteinogenic, form a strictly conserved hexapeptide backbone (Hüttel 2017). In contrast, variations at the side chains are frequent, most of them due to exchange by similar amino acids or incomplete hydroxyl
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