Biological Sciences
Echinocandins
Echinocandins are a class of antifungal drugs that work by inhibiting the synthesis of beta-glucan, a key component of the fungal cell wall. They are used to treat invasive fungal infections, particularly those caused by Candida and Aspergillus species. Echinocandins are considered a valuable treatment option due to their broad spectrum of activity and low toxicity.
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10 Key excerpts on "Echinocandins"
- Charles H. Nightingale, Paul G. Ambrose, George L. Drusano, Takeo Murakawa, Charles H. Nightingale, Paul G. Ambrose, George L. Drusano, Takeo Murakawa(Authors)
- 2007(Publication Date)
- CRC Press(Publisher)
18 Glucan Synthase Inhibitors Tawanda Gumbo University of Texas Southwestern Medical Center, Division of Infectious Diseases, Dallas, Texas, U.S.A. Fumiaki Ikeda Infectious Diseases Department, Pharmacology Research Laboratories, Drug Discovery Research, Astellas Pharma, Inc., Osaka, Japan Arnold Louie Emerging Infections and Pharmacodynamics Laboratory, Ordway Research Institute, Albany Medical College, Albany, New York, U.S.A. BRIEF HISTORY OF CLASS Echinocandins are a novel class of antifungal agents that were first isolated from the broth of Aspergillus species, including Aspergillus aculeatus and Aspergillus rugulovalvus , in the mid-1970s (1,2). The Echinocandins block cell wall formation by inhibiting the enzyme 1,3-b -D -glucan synthase, resulting in fungal death. These compounds are poorly absorbed through the gastrointestinal tract and, therefore, are administered intravenously. Since initial investigations centered on the ther-apeutic activity of these compounds against Pneumocystis carinii and Candida species, the compounds were named pneumocandins. However, the spectrum of activity includes some molds, including Aspergillus species (Table 1). The three Echinocandins that have reached clinical development are semisynthetic cyclic hexapeptides with N -linked fatty acyl side chains attached to pneumocandin B 0 (Fig. 1) (7). Caspofungin was the first echinocandin to be licensed for clinical use (in many countries, including the United States). Micafungin is licensed for clinical use in Japan and in the United States, and anidulafungin is licensed in the United States. The Echinocandins are an important addition to the antifungal armamentar-ium for several reasons. First Candida species are now responsible for approximately 10% of nosocomial bloodstream infections (8,9). The number of cases of candidemia and deep-seated candidal infections continue to rise as the number of immunosup-pressed patients increases.
- John S. Bradley, John D. Nelson, John S. Bradley, John D. Nelson(Authors)
- 2022(Publication Date)
- American Academy of Pediatrics(Publisher)
170 — Chapter 6. Choosing Among Antifungal Agents Choosing Among Antifungal Agents 6 Echinocandins This class of systemic antifungal agents was first approved in 2001. The Echinocandins inhibit cell wall formation (in contrast to acting on the cell membrane by the polyenes and azoles) by noncompetitively inhibiting beta-1,3-glucan synthase, an enzyme present in fungi but absent in mammalian cells. These agents are generally very safe, as there is no beta-1,3-glucan in humans. The Echinocandins are not metabolized through the CYP system, so fewer drug interactions are problematic, compared with the azoles. There is no need to adjust dose in renal failure, but one needs a lower dosage in the setting of very severe hepatic dysfunction. As a class, these antifungals generally have poor CSF penetra-tion, although animal studies have shown adequate brain parenchyma levels, and do not penetrate the urine well. While the 3 clinically available Echinocandins each individually have some unique and important dosing and pharmacokinetic parameters, especially in children, efficacy is generally equivalent. Opposite the azole class, the Echinocandins are fungicidal against yeasts but fungistatic against molds. The fungicidal activity against yeasts has elevated the Echinocandins to the preferred therapy against invasive candi-diasis. Echinocandins are thought to be best used against invasive aspergillosis only as salvage therapy if a triazole fails or in a patient with suspected triazole resistance, never as primary monotherapy against invasive aspergillosis or any other invasive mold infection. Improved efficacy with combination therapy with the Echinocandins and triazoles against Aspergillus infections is unclear, with disparate results in multiple smaller studies and a definitive clinical trial demonstrating minimal benefit over voriconazole monotherapy in only certain patient populations.
eBook - ePub- Mahmoud A. Ghannoum, John R. Perfect, 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
eBook - ePub- Martin Masuelli, Mauricio Filippa, Martin Masuelli, Mauricio Filippa(Authors)
- 2000(Publication Date)
- Bentham Science Publishers(Publisher)
18 ].Fig. (11)) A: Synthesis of β-(1,3)-D-glucan catalyzed by β-(1,3)-D-glucan synthase (GS). UDP-Glc: uridine diphosphate glucose. B: Chemical structures of clinical antifungal Echinocandins. C: Chemical structures of antifungal triterpenoids.Echinocandins non-competitively inhibit the Fks1p subunit, which results in the decrease of β-(1,3)-D-glucans in the fungal cell wall, leading to disruption of cell wall integrity, resulting in osmotic vulnerability and fungal cell death of Candida species [14 , 30 ]. In Aspergillus species, Echinocandins modify the hyphae morphogenesis and exert a fungistatic effect. They are recommended as a first-line treatment for esophageal and invasive candidiasis including candidemia and for invasive aspergillosis. Conversely, species belonging to Mucorales and basidiomycetes, like Cryptococcus spp., are intrinsically resistant to this antifungal class [1 , 30 ].The major advantages of Echinocandins over other drugs include their excellent safety profile and greater fungal selectivity because GS exists in fungi but is absent in mammalian cells. In addition, they exhibit a broad-spectrum activity because the genes encoding the catalytic subunits are present in diverse pathogenic fungi such as C. albicans, A. fumigatus, and P. brasiliensis [31 ].Rezafungin (CD101, SP3025) (Fig. 11B ) is a structural analog of anidulafungin, but with a choline moiety replacing the hemiaminal group at the C5 ornithine position, resulting in increased in vitro and in vivo stability compared to other Echinocandins and is also currently in clinical trials [31
- John R. Wingard, Elias Anaissie, John R. Wingard, Elias Anaissie(Authors)
- 2005(Publication Date)
- CRC Press(Publisher)
At the time of this writing, caspo-fungin is licensed, micafungin is on the verge of licensure, and anidulafungin is well into clinical trials. Drugs focused on this new antifungal target had reached the clinic. II. MECHANISM OF ACTION Although the cell wall has multiple components, beta-1,3-D -glucans are critical com-ponents for many (but not all) fungal species. Double deletion mutants of FKS1 (glucan synthase) are non-viable (11). Echinocandin-induced inhibition of glucan synthesis causes Candida cells to lose their rigidity, become deformed, and ultimately form a protoplast-like mass (Fig. 2) (22). Echinocandin binding may occur within moments, and an exposure of just minutes is sufficient to reduce cell viability sharply (Fig. 3) (23). One advantage of the Echinocandins is that they act independently of the fungal cell membrane. Thus, as expected, triazole-resistant Candida are susceptible Figure 1 Structures of Echinocandins. 486 Graybill and Anstead in vitro to Echinocandins (24–27). The Echinocandins have a long postantifungal effect, and are considered fungicidal to Candida (28,29). Unfortunately, this broad susceptibility does not apply to all fungi. Cryptococcus neoformans , also a yeast, does not contain high quantities of beta-1,3-D -glucans, and thus is resistant both in vitro and in animal models (30). Other investigators have found that overexpression of a gene coding for synthesis of a Golgi protein also confers resistance to caspofungin in Saccharromyces cerevesiae (31). Another potential advantage of Echinocandins is that they, and lipid prepara-tions of amphotericin B, appear unusually potent in reducing Candida in biofilms (32). This is of potential importance, as Candida are particularly difficult to treat when associated with prosthetic devices such as catheters and artificial heart valves (33,34). Whether this in vitro phenomenon can be translated into the clinical arena is unclear.
eBook - ePub- Awanish Kumar(Author)
- 2016(Publication Date)
- Academic Press(Publisher)
Beta-glucan destruction prevents resistance against osmotic forces, which leads to cell lysis. Treatment of fungi with β-glucan synthase inhibitors causes noncompetitive inhibition of 1, 3, β-glucan synthase with secondary effects on other constituents, such as an increase in the chitin content of the cell wall and a reduction in the ergosterol content of the fungal cell membrane [26]. They are sometimes referred to as “Penicillin of antifungals.” Caspofungin, micafungin, and anidulafungin are derivatives of Echinocandins of semisynthetic nature with emerging use due to their solubility, antifungal spectrum, and pharmacokinetic properties. The fact that resistance developed against this class of antifungals is rare makes it preferable. Also they are effective against FLU-resistant strains and fungicidal against most species of Candida. Echinocandins Variants Caspofungin It is a lipopeptide antifungal drug that is administered intravenously. It has potent activity on invasive infections. It was found to have notable effects against cell wall. Caspofungin has few significant interactions as it is neither a substrate nor an inhibitor of the cytochrome P-450 system. It blocks an enzyme that catalyzes the polymerization of uridine diphosphate-glucose into β (1–3) glucan. Micafungin It was approved for the treatment of oral candidiasis in the 2000s. It is also administered intravenously for prophylaxis treatment in patients of candidemia, acute disseminated candidiasis, Candida peritonitis, abscesses, and esophageal candidiasis. Anidulafungin Anidulafungin is a semisynthetic candin. It has proven efficacy against esophageal candidiasis, but its main use will probably be in invasive Candida infection. Pneumocandins Pneumocandins are lipohexapeptides of the echinocandin family that potently interrupt fungal cell wall biogenesis by noncompetitive inhibition of 1,3-β-glucan synthase [27]. Echinocandin B It was the first of the echinocandin class of antifungals
- John S. Bradley, John D. Nelson, John S. Bradley, John D. Nelson(Authors)
- 2024(Publication Date)
- American Academy of Pediatrics(Publisher)
These agents are generally very safe, as there is no beta-1,3-glucan in humans. The Echinocandins are not metabolized through the CYP system, so fewer drug interactions are problematic, compared with the azoles. There is no need to adjust dose in renal failure, but one needs a lower dosage in the setting of very severe hepatic dysfunction. As a class, these antifungals generally have poor CSF penetration, although animal studies have shown adequate brain parenchyma levels, and do not penetrate the urine well. While the 3 clinically available Echinocandins each individually have some unique and important dosing and PK parameters, especially in children, efficacy is generally equivalent. Opposite the azole class, the Echinocandins are fungicidal against yeasts but fungistatic against molds. The fungicidal activity against yeasts has elevated the Echinocandins to the preferred therapy against invasive candi- diasis. Echinocandins are thought to be best used against invasive aspergillosis only as salvage therapy if a triazole fails or in a patient with suspected triazole resistance, never as primary monotherapy against invasive aspergillosis or any other invasive mold infection. Improved efficacy with combination therapy with the Echinocandins and triazoles against Aspergillus infections is unclear, with disparate results in multiple smaller studies and a definitive clinical trial demonstrating minimal benefit over voriconazole monotherapy in only certain patient populations. Some experts have used combination therapy in invasive aspergillosis with a triazole plus echinocandin only during the initial phase of waiting for triazole drug levels to be appropriately high. There are reports of echinocandin resistance
eBook - ePubHigh Value Fermentation Products, Volume 1
Human Health
- Saurabh Saran, Vikash Babu, Asha Chaubey, Saurabh Saran, Vikash Babu, Asha Chaubey(Authors)
- 2019(Publication Date)
- Wiley-Scrivener(Publisher)
Thus, with few exceptions [66], it is never used as monotherapy but always in combination with another antifungal, such as amphotericin B [83, 84]. However, the elevated renal and liver toxicities of amphotericin B, that further increase 5-FC hepatotoxicity, has led to combination therapy of 5-FC with azole drugs. Echinocandins – The first echinocandin-type antimycotic, echinocandin B, was isolated independently by the researchers of Ciba-Geigy, Sandoz and Eli Lilli from the fermentation broth of “Aspergillus nidulans var. echinolatus”, “Aspergillus nidulans var. roseus” and Aspergillus rugulosus in the 1970s in random screening of the available strain collections [85–87]. Echinocandin B was followed by the isolation and characterization of more than 20 natural Echinocandins. All these secondary metabolites are produced by ascomycota fungi (Table 5.6). They possess cyclic lipo-hexapeptide N-acylated structure with an aliphatic chain of different length [88, 89]. The various Echinocandins differ in having different substituents in the hexapeptide ring or a distinct fatty acid chain. This latest class of antifungals is currently represented by three drugs – caspofungin, micafungin and anidulafungin. These drugs affect cell wall biosynthesis by noncompetitive inhibition of β-1,3-glucan synthase [90–92]. Echinocandins show a high heterogeneity in the number and position of hydroxyl-groups on L-Orn, L-homoTyr, L-Gln and (mehyl)-L-Pro and/or the presence of the methyl-group on L-Pro even within the main groups. Because of high-complex chemical structure Echinocandins possess their industrial-scale production is based on fermentation. Among the natural Echinocandins, echinocandin B, pneumocandin B0 and FR901379 are produced for commercial purposes. Since the fermentation and purification costs of natural Echinocandins are the primary reason for the high costs of semisynthetic derivatives, the optimization of the fermentation process is crucial to make a competitive product
eBook - PDF- Dilip K. Arora(Author)
- 2003(Publication Date)
- CRC Press(Publisher)
In addition, it enhances the activity of amphotericin B against C. neoformans and Aspergillus spp., suggesting that this may be useful in combination with this established antifungal Antifungal drugs in fungal infections 789 Figure 4 (a) Chemical structures and antifungal targets of important classes (polyene, benzofuran cyclohexene, pyrimidine, thiocarbamate, and imidazole) of antifungal agents. Antifungal targets are shown in parentheses. (b) Chemical structures and antifungal targets of important classes (triazole, allylamine, benzylamine, morpholine, and echinocandin) of antifungal agents. Antifungal targets are shown in parentheses. agent (Franzot and Casadevall 1997; Arikan et al. 2002). The most recent echinocandin Handbook of fungal biotechnology 790 entering clinical trials is FK463. Although published data on it are limited, the agent seems to be similar to caspofungin. FK463 displays substantial antifungal activity against both Candida spp. and Aspergillus spp. (Tawara et al. 2000), and proved efficacious in several animal models of systemic fungal infections (Ikeda et al. 2000; Maesaki et al. 2000; Matsumoto et al. 2000). FK463, like other Echinocandins, have also proved active against azole-resistant strains of Candida albicans expressing CDR1 or CaMDR (Maesaki et al. 2000). Since these Echinocandins are generally well tolerated and free from significant interaction with cytochrome P450 (Groll and Walsh 2001), they appear as promising candidates for the next generation of antifungal agents. 7 CONCLUSIONS Efforts have been made to discover desirable antifungal agents with selectivity to pathogenic fungi since the beginning of the twentieth century, and such potent antifungal agents as undecylenic acid, griseofulvin, 5-FC, polyene derivatives (nystatin and amphotericin B), thiocarbamate Antifungal drugs in fungal infections 791
eBook - PDF- Doblin Sandai(Author)
- 2019(Publication Date)
- IntechOpen(Publisher)
The mechanism of Candida resistence to the polyenes are not yet known, but seem to involve changes in the cell membrane composition [15]. Echinocandins are noncompetitive inhibitors of the β -1,3 glucan synthase encoded by the FKS1 gene of C. albicans , which leads to the formation of fungal cell walls with impaired struc-tural integrity, leading to osmotic lysis. Resistance is associated with acquired or intrinsic Primary forms of oral candidiasis Characteristics Pseudomembranous candidiasis (oral thrush) Confluent white plaques with epithelial desquamation and accumulation of keratin, fibrin, necrotic tissue, and fungal hyphae [ 5, 11] • Ability to easily remove white plaques with gauze [5] • Most commonly found in immunosuppressed individuals [ 5] Acute erythematous oral candidiasis • Known as “sore mouth antibiotic,” due to its association with prolonged use of broad-spectrum antibiotics [11] • It presents as erythematous patches, commonly on the palate, but may also present on the buccal mucosa or on the back of the tongue [5] Chronic erythematous oral candidiasis • These are atopic lesions associated with angular cheilitis and prosthetic stomatitis [5] • Prevalence in HIV-positive and AIDS patients [ 11] Chronic hyperplastic candidiasis (candida leukoplakia) • Homogeneous type of adherent white or erythematous nodular/speckled type that cannot be easily erased [5, 11] • It is present bilaterally in the commissure regions of the buccal mucosa [11] Table 1. Primary forms of oral candidiasis [ 10]. Figure 1. Primary targets of several antifungal agents by Garcia-Cuesta et al. [ 14]. Antifungal Activity of Brazilian Medicinal Plants against Candida Species http://dx.doi.org/10.5772/intechopen.80076 21 FKS1 point mutations [15]. Flucidosycin is a pyrimidine analogue, which is transported to fungal cells by cytosine permeases. After this, 5-fluorouracil and phosphorylation of 5-fluoro -deoxyuridine monophosphate are deaminated.
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