Echinocandins: production and applications

Abstract

The first echinocandin-type antimycotic (echinocandin B) was discovered in the 1970s. It was followed by the isolation of more than 20 natural echinocandins. These cyclic lipo-hexapeptides are biosynthesized on non-ribosomal peptide synthase complexes by different ascomycota fungi. They have a unique mechanism of action; as non-competitive inhibitors of β-1,3-glucan synthase complex they target the fungal cell wall. Results of the structure-activity relationship experiments let us develop semisynthetic derivatives with improved properties. Three cyclic lipohiexapeptides (caspofungin, micafungin and anidulafungin) are currently approved for use in clinics. As they show good fungicidal (Candida spp.) or fungistatic (Aspergillus spp.) activity against the most important human pathogenic fungi including azole-resistant strains, they are an important addition to the antifungal armamentarium. Some evidence of acquired resistance against echinocandins has been detected among Candida glabrata strains in recent years, which enhanced the importance of data collected on the mechanism of acquired resistance developing against the echinocandins. In this review, we show the structural diversity of natural echinocandins, and we summarize the emerging data on their mode of action, biosynthesis and industrial production. Their clinical significance as well as the mechanism of natural and acquired resistance is also discussed.

Structural diversity in echinocandin biosynthesis: the impact of oxidation steps and approaches toward an evolutionary explanation

“…Some of these strains have also been cultivated on a technical scale [3], so that echinocandin byproducts produced in low concentrations could be isolated and structurally characterized. This section provides an overview of the echinocandin producer strains described so far and their diverse products.…”

“…Although natural echinocandins are not of clinical use due to their toxicity and low solubility, chemical derivatives such as caspofungin, anidulafungin, and micafungin are most important drugs for the treatment of invasive mycoses. The pharmacological use of echinocandins has been reviewed in several overview articles [1][2][3][4]. In Table 1, some properties of echinocandins applied in therapy are summarized.…”

Evolution of Chemical Diversity in Echinocandin Lipopeptide Antifungal Metabolites

“…1 and 2) has been investigated for 4 decades and forms the molecular platform for a successful class of cell wall-active antifungal drugs (8)(9)(10)(11)(12). Their mode of action is the noncompetitive inhibition of the ␤-1,3-glucan synthase complex; thus, they interrupt synthesis of a primary cell wall structural polymer.…”

Albumin Enhances Caspofungin Activity against Aspergillus Species by Facilitating Drug Delivery to Germinating Hyphae

“…chinocandins comprise a group of cell wall-active antifungal agents targeting ␤-1,3 glucan synthase that display potent antifungal activity against Candida and Aspergillus species (1)(2)(3)(4). Caspofungin is the first member of this class of antifungal compounds that has been approved as first-line therapy for invasive candidiasis and as salvage therapy for invasive aspergillosis.…”