Echinocandins: structural diversity, biosynthesis, and development of antimycotics

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.

Ribosomally derived lipopeptides containing distinct fatty acyl moieties

“…Lipopeptides are a widespread class of bioactive natural products in bacteria and fungi ( 1 – 3 ). They consist of a hydrophobic moiety comprising predominantly fatty acyl units of various lengths and functionalization, linked to a hydrophilic peptide portion that is often cyclized and/or contains nonproteinogenic amino acids.…”

“…Lipopeptides fulfill diverse ecological roles [e.g., as biosurfactants, in biofilm formation, and to access nutrients ( 4 , 5 ) and as mediators of interspecies interactions that include defense against predators, competition, pathogenicity, and symbiosis ( 1 , 6 , 7 )]. Relevant examples are the surfactin-type biosurfactants, orfamides and fengycins that induce systemic resistance in plants, and the antifungal echinocandins ( 1 , 3 , 8 , 9 ). Lipopeptides have important medical and industrial applications as antimicrobial, antitumor, drug-delivery, and vaccine agents ( 2 , 8 , 9 ), among which daptomycin, polymyxin, and echinocandin are prominent representatives of antibiotics in clinical use.…”

Cyclic peptide drugs approved in the last two decades (2001–2021)

“…They share the same cyclic peptide core structure by targeting the enzyme 1,3β-glucan synthase for synthesizing glucan in the cell wall [139,140]. The cyclization was formed by amidation between the sidechain of the first N-terminal residue of Lysine and the C-terminus of the peptide chain [141]. All three antifungal drugs have clinical efficacy against invasive candidiasis and other forms of systemic mycoses [142].…”

Repurposing Antifungals for Host-Directed Antiviral Therapy?

“…Inhibit the fungal enzyme β1,3-glucan synthase, leading to incomplete fungal cell wall formation [17].…”