Synthesis of new analogs of echinocandin B by enzymatic deacylation and chemical reacylation of the echinocandin B peptide: Synthesis of the antifungal agent cilofungin (LY121019).

Debono, Manuel; Abbott, Bernard J.; Fukuda, D. S.; Barnhart, M.; Willard, K. E.; Molloy, Robert; Michel, Karl-Heinz; Turner, J. R.; Butler, Thomas F.; Hunt, Ann H.

doi:10.7164/antibiotics.42.389

Cited by 57 publications

(19 citation statements)

References 10 publications

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“…Echinocandin B, pneumocandin B0 and other echinocandin lipopeptides are structurally characterized by a cyclic hexapeptide acylated with a long side chain, and have an excellent anti-Candida activity attributed to selective inhibition of 1,3-b-glucan synthesis, although their intrinsic water insolubility is a major barrier for drug development. [17][18][19] However, FR901379 and related compounds showed both high water solubility and a strong antifungal effect on Candida spp. 20 The structural difference between FR901379 and the other echinocandins is that FR901379 has a sulfate moiety in its molecule (Figure 1, circled).…”

Section: Discovery Of Fr901379mentioning

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: Discovery Of Fr901379mentioning

confidence: 99%

Micafungin: a sulfated echinocandin

Hashimoto

2009

J Antibiot

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“…7 While 1 and family members subsequently isolated, such as pneumocandin A 0 4, 8 aculeacin, 9 cryptocandin, 10 and mulundocandin 11 , show anti- Candida activity, the hemolytic properties of natural echinocandins prevented their use as therapeutics. Derivatization of 1 and 4 , especially in the fatty acid moiety, led to the development of cilofungin 2 , 12–13 anidulafungin 3 (Eraxis, Pfizer), 14 caspofungin (Cancidas, Merck and Co) 5 , 15 and micafungin 6 (Mycamine, Astellas Pharma) 16 (Scheme 1) that have less hemolytic properties while retaining the bioactivity of their parent compound. For example, 3 , a semisynthetic derivative of 1 containing a substituted terphenyl acyl chain, was approved by the FDA in 2006.…”

Section: Introductionmentioning

confidence: 99%

Identification and Characterization of the Echinocandin B Biosynthetic Gene Cluster from Emericella rugulosa NRRL 11440

et al. 2012

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Echinocandins are a family of fungal lipidated cyclic hexapeptide natural products. Due to their effectiveness as antifungal agents, three semisynthetic derivatives have been developed and approved for treatment of human invasive candidiasis. All six of the amino acid residues are hydroxylated, including 4R,5R-dihydroxy-L-ornithine, 4R-hydroxyl-L-proline, 3S,4S-dihydroxy-L-homotyrosine, and 3S-hydroxyl,4S-methyl-L-proline. We report here the biosynthetic gene cluster of echinocandin B 1 from Emericella rugulosa NRRL 11440 containing genes encoding for a six-module nonribosomal peptide synthetase EcdA, an acyl-AMP ligase EcdI and oxygenases EcdG, EcdH and EcdK. We showed EcdI activates linoleate as linoleyl-AMP and installs it on the first thiolation domain of EcdA. We have also established through ATP:PPi exchange assay that EcdA loads L-ornithine in the first module. A separate hty gene cluster encodes four enzymes for de novo generation of L-homotyrosine from acetyl-CoA and 4-hydroxy-phenyl-pyruvate is found from the sequenced genome. Deletions in the ecdA, and htyA genes validate their essential roles in echinocandin B production. Five predicted iron-centered oxygenase genes, ecdG, ecdH, ecdK, htyE, htyF, in the two separate ecd and hty clusters are likely to be the tailoring oxygenases for maturation of the nascent NRPS lipohexapeptidolactam product.

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“…Full biological activity seems to require both the cyclic structure [92] and an acyl side chain, emphasizing the importance of the acyl group for the mode of action [93,94].…”

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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Synthesis of new analogs of echinocandin B by enzymatic deacylation and chemical reacylation of the echinocandin B peptide: Synthesis of the antifungal agent cilofungin (LY121019).

Cited by 57 publications

References 10 publications

Micafungin: a sulfated echinocandin

Micafungin: a sulfated echinocandin

Identification and Characterization of the Echinocandin B Biosynthetic Gene Cluster from Emericella rugulosa NRRL 11440

Lipopeptides as anti-infectives: a practical perspective

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