Echinocandins

3 Key excerpts on "Echinocandins"

• 

  eBook - ePub

  Antifungal Therapy, Second Edition

  • Mahmoud A. Ghannoum, John R. Perfect(Authors)
  • 2019(Publication Date)
  • CRC Press

    (Publisher)

  These agents block fungal cell wall synthesis through inhibition of (1,3)-beta-D-glucan synthase, resulting in fungicidal effects against Candida spp. and fungistatic effects against Aspergillus spp. Echinocandins have also been shown to have some activity, alone or in combination with other agents, against a variety of other fungal pathogens. Several clinical trials have evaluated performance of Echinocandins in the setting of oropharyngeal/esophageal candidiasis and invasive candidiasis. Others have reported experience with Echinocandins as salvage therapy for invasive aspergillosis, and case reports describe efficacy of these agents in the treatment of a variety of other fungal infections. In general, Echinocandins have become preferred agents in the hospital setting for invasive candidiasis because of broad activity against non-albicans Candida as well as Candida albicans infections, while having an excellent safety profile and relative lack of drug interactions. Since they are available only in intravenous form, their use is limited in patients where oral antifungal therapy is preferable. CHEMICAL STRUCTURE AND FORMULATIONS Structurally, Echinocandins are all large lipoprotein molecules containing an amphiphilic cyclic hexapeptide. All three Echinocandins have a unique N -linked acyl lipid side chain, which imparts different physicochemical properties to each agent [ 1, 2 ]. Caspofungin was derived from Glarea lozoyensis, while micafungin and anidulafungin are fermentation by-products of the fungi Coleophoma empetri F-11899 and Aspergillus nidulans, respectively [ 2, 3, 4, 5 ]. Owing to their lipophilicity and large size, Echinocandins have low bioavailability and, therefore, are only available for parenteral (intravenous) delivery. With its fatty acid side chain, caspofungin is soluble in water. Similarly, micafungin is soluble in water due to it complex aromatic side chain. In contrast, anidulafungin is insoluble in water due to its alcoxytriphenyl side chain

  Sign up to read

  Learn more about book
• 

  eBook - ePub

  High Value Fermentation Products, Volume 1

  Human Health

  • Saurabh Saran, Vikash Babu, Asha Chaubey(Authors)
  • 2019(Publication Date)
  • Wiley-Scrivener

    (Publisher)

  Glucan, a polysaccharide constituted by glucose monomers linked by (1,3)-β or (1,6)-β bonds, is an essential component of the cell wall [107]. Echinocandins are reported to be potent glucan synthesis inhibitors. The success of the lipopeptide class of glucan synthesis inhibitors has prompted the search for other antifungal agents with improved features over the Echinocandins (lack of oral absorption). Other cyclic peptides like arborcandins have been described as as glucan synthesis inhibitors. These contain a 10-amino-acid ring and two lipophilic tails [108] like FR901469 (macrocyclic lipopeptidolactone) composed of 12 amino acids and a 3-hydroxypalmitoyl moiety [109]. However, besides cyclic lipopeptides, only two other types of glucan synthesis inhibitors are known, the papulacandins and related compounds, and the acidic triterpenes. The papulacandins are glycolipids discovered in the late 1970s [110, 111]. Despite medicinal chemistry efforts, neither papulacandins nor any of their relatives have been developed as drugs, basically due to their limited potency in animal models [112]. The most recently discovered compound class of glucan synthesis inhibitors are triterpenes containing a polar (acidic) moiety [113]. This polar moiety can be a glycoside (in enfumafungin and ascosteroside), a succinate (in arundifungin) or a sulphate-derivative amino acid (in ergokonin A).

  The main effect of Echinocandins is glucan inhibition of cell wall but a secondary effect is obtained by reduction of ergosterol (Figure 5.3 ) and lanosterol content with increased chitin content. This produces cytological and ultrastructural changes, such as growth of pseudohyphae, thickened cell wall, buds failing to separate from mother cells, cells becoming osmotically sensitive and restriction of lysis to the growing tips of budding cells [114, 115].
• Chitin synthesis inhibitors
  Chitin is an insoluble polysaccharide made of β-(1,4)-linked N-acetylglucosamine units. This biological polymer is one of the structural microfibrillar components of the fungal cell wall structure which maintains the morphological shape of the cells and plays an essential role in fungal morphogenesis [116]. In yeasts, chitin accounts for 1% of the cell wall and is distributed differently from glucan. Chitin also links covalently to the cellular glucan, thereby strengthening the wall. There are at least three different chitin synthases; chitin synthase I, involved in repair function during cytokinesis; chitin synthase II, playing a role in primary septum formation between mother and daughter cells; and chitin synthase III, synthesizing lateral chitin in the cell wall [117]. Nikkomycins and polyoxins (peptide-nucleoside antimycotic agents) are well-known inhibitors of chitin synthesis [118].
• Mannoprotein synthesis inhibitors
  Mannoproteins form the outer layer of the cell wall and contain about 50% carbohydrate. The majority of the cell wall mannoproteins are anchored by β-(1,6)- and β-(1,3)-glucan [119] and play several roles in the function of fungal membranes. Inhibitors of the mannoproteins function are the pradimicin/benanomycinfamily, whose chemical structure possesses a benzo [a] naphthacenequinone skeleton [120, 121]. The free carboxyl group of these compounds interacts with the saccharide portion of cell-surface mannoprotein, which disrupts the plasma membrane and causes leakage of intracellular potassium.