Synthesis and Evaluation of LY121019, a Member of a Series of Semisynthetic Analogues of the Antifungal Lipopeptide Echinocandin Ba

Debono, Manuel; Abbott, Bernard J.; Turner, J. R.; Howard, Leonard C.; Gordee, Robert S.; Hunt, Alauna; Barnhart, M.; Molloy, Robert; Willard, K. E.; Fukuda, D. S.; Butler, Thomas F.; Zeckner, Douglas J.

doi:10.1111/j.1749-6632.1988.tb40398.x

Cited by 72 publications

(21 citation statements)

References 20 publications

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“…Such operations were initiated by Lilly on echinocandin B to yield cilofungin. 9 This compound was subjected to Phase II clinical trials, but was abandoned due to toxicity. Further modification of the structure by converting the phenolic hydroxyl to a sodium phosphate ester produced the more soluble prodrug LY307853, which resulted in the active form, LY303366.…”

Section: Introductionmentioning

confidence: 99%

Micafungin: a sulfated echinocandin

Hashimoto

2009

J Antibiot

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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.

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Section: Introductionmentioning

confidence: 99%

Micafungin: a sulfated echinocandin

Hashimoto

2009

J Antibiot

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“…With the reintroduction of the N-acyl group, the biological activity was restored, as long as certain structural requirements were met. Indeed, while small groups such as acetyl, benzoyl or cyclohexanoyl were ineffective in restoring activity, increase in the chain length from C 12 up to C 17 -C 18 , was proportional with an increase in activity [95,96].…”

Section: Echinocandinsmentioning

confidence: 99%

Lipopeptides as anti-infectives: a practical perspective

et al. 2009

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Abstract:Lipopeptide antibiotics represent an old class of antibiotics that were discovered over 50 years ago, which includes the old polymyxins but also new entries, such as the recently approved daptomycin. They generally consist of a hydrophilic cyclic peptide portion attached to a fatty acid chain which facilitates insertion into the lipid bilayer of bacterial membranes. This review presents an overview of this class of antibiotics, focusing on their therapeutic applications and putting particular emphasis on chemical modifications introduced to improve their activity.

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“…ECB can be modified by enzymatic deacylation to a cyclic hexapeptide without a linoleoyl side chain and by subsequent chemical reacylation to generate a few therapeutic antifungal agents for clinical practice, such as anidulafungin (12)(13)(14)(15). A deacylase from Actinoplanes utahensis NRRL 12052 catalyzes the cleavage of the linoleoyl side chain from ECB ( Fig.…”

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confidence: 99%

Efficient Bioconversion of Echinocandin B to Its Nucleus by Overexpression of Deacylase Genes in Different Host Strains

Shao

Liu

et al. 2013

Appl Environ Microbiol

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b Anidulafungin, which noncompetitively inhibits ␤-(1,3)-D-glucan synthase in fungal cell wall biosynthesis, is the newest antifungal drug to be developed. Echinocandin B deacylase from Actinoplanes utahensis NRRL 12052 catalyzes the cleavage of the linoleoyl group of echinocandin B, a key step in the process of manufacturing anidulafungin. Unfortunately, the natural yield of echinocandin B nucleus is low. In our study, the echinocandin B deacylase gene was systematically overexpressed by genetic engineering in its original producer, A. utahensis, and in the heterologous hosts Streptomyces lividans TK24 and Streptomyces albus. The introduction of additional copies of the gene, under the control of PermE* or its native promoter, into hosts showed significant increases in its transcription level and in the efficiency of the bioconversion of echinocandin B to its nucleus. The conditions for the cultivation and bioconversion of A. utahensis have been optimized further to improve production. As a result, while the wild-type strain initially produced 0.36 g/liter, a concentration of 4.21 g/liter was obtained after the generation of a strain with additional copies of the gene and further optimization of the reaction conditions. These results are useful for enhancing echinocandin B nucleus production in A. utahensis. Our study could enable the engineering of commercially useful echinocandin B nucleus-overproducing stains.

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Synthesis and Evaluation of LY121019, a Member of a Series of Semisynthetic Analogues of the Antifungal Lipopeptide Echinocandin Ba

Cited by 72 publications

References 20 publications

Micafungin: a sulfated echinocandin

Micafungin: a sulfated echinocandin

Lipopeptides as anti-infectives: a practical perspective

Efficient Bioconversion of Echinocandin B to Its Nucleus by Overexpression of Deacylase Genes in Different Host Strains

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