Micafungin: a sulfated echinocandin

Abstract

Micafungin is the second approved antifungal agent in the echinocandin series and is now used worldwide in chemotherapy for life-threatening fungal infections. It is water-soluble and is semi-synthesized from the acylated cyclic hexapeptide FR901379, a natural product from the fungus Coleophoma empetri F-11899, through enzymatic deacylation of FR901379, followed by chemical reacylation with the optimized N-acyl side chain. The water solubility of micafungin is ascribed to a sulfate moiety in the molecule. This feature differentiates micafungin from other echinocandin members. Micafungin is a potent inhibitor of 1,3-b-glucan synthase, an enzyme necessary for cell-wall synthesis of several fungal pathogens. The Journal of Antibiotics (2009) and Cryptococcus neoformans are a threat to human health. Incidences of these systemic fungal infections have increased significantly over the past few years. The major reasons for this dramatic increase are the extensive use of broad-spectrum antibiotics and the growing number of immunocompromised patients with acquired immunodeficiency syndrome (AIDS), cancer and transplants. 1,2 In the mid 1900s, few compounds, such as polyenes (for example, nystatin and amphotericin B) and flucytosine, were available for antifungal chemotherapy. Although the development of azole drugs started in the early 1970s, only a limited number of antifungal agents were available for treatment of life-threatening fungal infections. Moreover, the existing agents had disadvantages, such as the significant nephrotoxicity of amphotericin B 3 and the emergence of resistance to the azoles. 4 To overcome these defects, lipid formulations of polyenes were developed to reduce toxicity, and new triazoles (for example, voriconazole, ravuconazole and posaconazole) were developed to improve the antifungal spectra or susceptibility to azoleresistant isolates. 5 Despite a number of therapeutic advancements, there was a need to develop a new class of antifungal agents with novel mechanisms of action.

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

“…Brought to you by | MIT Libraries Authenticated Download Date | 5/12/18 7:55 PM Table 5: Fungal strains producing echinocandins (see also [25] compounds, see Hashimoto [59]; for 'WF' classification, see Hino et al [42].…”

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.…”

“…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. Two of the variable features of the echinocandin family, acyl side chain methylation and homotyrosine sulfation (10,11), critically shaped the development paths to the final drugs. Palmitoyl or linoleoyl linear side chains, such as those of echinocandin B and FR901379, were significantly more hemolytic than the 10,12-methyl myristoyl branched side chain of pneumocandin B 0 and necessitated strategies for side chain deacylation and synthetic replacement.…”

Cloning and expression of the FR901379 acylase gene from Streptomyces sp. no. 6907

“…4 Micafungin, 5 which we developed commercially at Astellas, has been used worldwide in chemotherapy regimens to treat life-threatening fungal infections. This compound is semi-synthesized from acylated cyclic hexapeptide FR901379, 6 a natural product of the fungus Coleophoma empetri F11899, via enzymatic deacylation of FR901379 followed by chemical reacylation with an optimized N-acyl side chain.…”