Fungal ß(1,3)-D-glucan synthesis

Douglas, C. M.

doi:10.1080/714031000

Cited by 70 publications

(97 citation statements)

References 73 publications

(135 reference statements)

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“…It is postulated to be the catalytic subunit, although little is known about the structure and function of glucan synthase (Douglas, 2001). Resistance mutations in HS1 fall within an 89 amino acid domain that is predicted to lie on the cytoplasmic face of the plasma membrane.…”

Section: Fks1 the Resistance Targetmentioning

confidence: 99%

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Resistance to echinocandin-class antifungal drugs

Perlin¹

2007

Drug Resistance Updates

460

400

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Invasive fungal infections cause morbidity and mortality in severely ill patients, and limited drug classes restrict treatment choices. The echinocandins drugs are the first new class of antifungal compounds that target the fungal cell wall by blocking β-1,3-D-glucan synthase. Elevated MIC values with occasional treatment failure have been reported for strains of Candida. Yet, an uncertain correlation exists between clinical failure and elevated MIC values for the echinocandin drugs. Fungi display several adaptive physiological mechanisms that result in elevated MIC values. However, resistance to echinocandin drugs among clinical isolates is associated with amino acid substitutions in two "hot-spot" regions of Fks1, the major subunit of glucan synthase. The mutations, yielding highly elevated MIC values, are genetically dominant and confer cross-resistance to all echinocandin drugs. Prominent Fks1 mutations decrease the sensitivity of glucan synthase for drug by one thousand-fold or more, and strains harboring such mutations may require a concomitant increase in drug to reduce fungal organ burdens in animal infection models. The Fks1-mediated resistance mechanism is conserved in a wide variety of Candida spp. and can account for intrinsic reduced susceptibility of certain species. Fks1 mutations confer resistance in both yeasts and moulds suggesting that this mechanism is pervasive in the fungal kingdom.

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Section: Fks1 the Resistance Targetmentioning

confidence: 99%

“…A mechanism for clinically-relevant resistance is expected to reflect direct changes in drug-target interactions. Unfortunately, the mechanistic nature of echinocandin inhibition of glucan synthase is poorly understood, as is biochemistry of the glucan synthase complex (Douglas, 2001). …”

Section: Considerations For a Drug Resistance Mechanism Of Clinical Imentioning

confidence: 99%

Resistance to echinocandin-class antifungal drugs

Perlin¹

2007

Drug Resistance Updates

460

400

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“…De acordo com Douglas (2001), a polimerização dos açúcares é gradativa, sendo adicionada uma unidade de glucose por vez, até se formar as longas cadeias. Na parede celular de algumas leveduras, como Cândida dubliniensis, foi encontrado um componente majoritário rico em manose associado a uma proteína, constituindo as manoproteínas.…”

Section: Polissacarídeos De Parede Celular Fúngicaunclassified

Polissacarídeos de parede celular fúngica: purificação e caracterização

et al. 2009

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ResumoA parede celular é uma estrutura rígida, essencial para a sobrevivência dos fungos, e o conhecimento de sua composição poderá ser útil para o desenvolvimento de novas drogas antifúngicas. Neste contexto, os polissacarídeos estão entre os seus principais componentes que têm sido alvos de intensa investigação científica. As informações, provenientes do conhecimento da estrutura dessas macromoléculas, poderão ser valiosas para o entendimento dos mecanismos de síntese da parede celular de fungos causadores de patologias, tanto em plantas quanto em animais. A determinação da estrutura química de um endopolissacarídeo deve ser precedida por experimentos de extração e purificação. As extrações, geralmente conduzidas em soluções aquosas neutras e/ou alcalinas, separaram as biomoléculas em grupos, de acordo com suas solubilidades. Os extratos, contendo mistura de polissacarídeos, podem ser purificados pela combinação de métodos químicos e cromatográficos. Após purificação, os polissacarídeos considerados homogêneos são caracterizados estruturalmente com as técnicas convencionais em química de carboidratos tais como hidrólise, metilação, FT-IR e RMN- 13C e 1 H. Esta revisão tem como proposta efetuar um levantamento das principais investigações científicas conduzidas com o objetivo de caracterizar polissacarídeos da parede celular fúngica. Palavras-chave: Biomassa, parede celular fúngica, polissacarídeos, caracterização química AbstractThe cell wall is a rigid structure essential for the survival of fungi. A knowledge of its composition is therefore useful for the development of novel anti-fungal drugs. In this context, polysaccharides as main components of the fungal cell wall have been the subject of intense scientific study over the years. The information gained from the knowledge of the structure of these macrobiomolecules could therefore be valuable in elucidating the mechanisms of their biosynthesis in the cell walls of pathogenic fungi infecting plants and animals alike. Determination of the chemical structures of these polysaccharides (endo) is preceded by their extraction and purification. The extractions, generally lead to neutral and/ or alkaline soluble biopolymers in groups according to their solubilities. Mixtures of polysaccharides in these extracts can then be purified by a combination of chemical and chromatographic methods.

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“…El blanco de las equinocandinas es el complejo de síntesis de la pared celular fúngica β-1,3-Dglucano sintetasa 18 . En base a tal mecanismo se ha planteado una homología con penicilina y sus derivados que actúan sobre transpeptidasas y sintetasas en la pared bacteriana (PBP), por lo que algunos autores insinúen que las equinocandinas serán las "penicilinas antifúngicas".…”

Section: Mecanismos De Acciónunclassified

Nuevos antifúngicos: Las equinocandinas

2004

Rev. chil. infectol.

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The lipopeptide family known as echinocandins emerge as the new "antifungal penicillins", because their ability to destroy the fungal cell wall as they inhibit glucan synthesis, the main component of fungal structure. Echinocandins are fungicidal in vitro and in vivo against most Candida species and fungistatic against Aspergillus sp, without antifungal activity over mammal cells. Three drugs are representative of this class; caspofungin, micafungin and anidulafungin, the two first have been licensed for human use. Their optimal security profile, with low incidence and severity of adverse effects, kind posology and few interactions with other drugs, represent noticeable advantages for modern antifungal therapy. They have similar clinical efficacy as amphotericin B, without its toxicity, which besides the absence of antagonism with other antifungal drugs, allows to suggest that combined antifungal therapy could represent a new standard for the management of the feared invasive aspergillosis.Key words: Echinocandins; Caspofungin; Micafungin; Anidulafungin. Palabras claves: Equinocandinas; Caspofungina; Micafungina; Anidulafungina. IntroducciónEn las últimas décadas asistimos a la emergencia de los hongos como patógenos oportunistas humanos. Sobre 7% de los pacientes en hospitales universitarios europeos fallecen de aspergilosis y diversas especies de Candida se han constituido en causa común de infección nosocomial 1,2 . Ciertos grupos de pacientes inmunocomprometidos presentan alto riesgo de micosis severas; por ejemplo, 15% de los receptores de trasplante alogeneico de células madres 3 , y casi 20% de los sometidos a trasplantes pulmonares, están colonizados o infectados 4 ; en los pacientes con SIDA de países desarrollados la neumonía por Pneumocystis jiroveci (ex P. carinii) y la candidiasis esofágica alcanzan incidencias de 60 y 20% respectivamente 5 . En Chile, Lucero y cols reportan 9,2% de infecciones fúngicas profundas en niños con episodios de neutropenia febril 6 ; por otro lado, Wolff y cols 7 reportan que en el seguimiento de una cohorte de 166 pacientes adultos con infección por VIH y sin terapia antiretroviral, 17,2% por año presentó candidiasis esofágica, 9,1% por año neumonía por P. jiroveci y 4,1% por año criptococosis meníngea.Diversos factores dan cuenta de este aumento en las infecciones fúngicas, a saber, el mejor manejo de otras complicaciones de la inmunodepresión, nuevos y cada vez más agresivos regímenes inmunosupresores, mayor sobrevida en pacientes de unidades de cuidados críticos, alta incidencia de procedimientos invasores y cateterizaciones, mayor sospecha clínica, mejores métodos diagnósticos y el uso exagerado de antimicrobianos.A la fecha, el manejo de las infecciones micóticas sistémicas se sostiene en tres grupos de antifúngicos; polienos (anfotericina B), azoles (itraconazol, fluconazol, voriconazol, entre otros) y la fluocitosina (no disponible en Chile) (Tabla 1). A pesar del importante aporte de estos fármacos al manejo de las infecciones fúngicas, los índices de fracaso ele...

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Fungal ß(1,3)-D-glucan synthesis

Cited by 70 publications

References 73 publications

Resistance to echinocandin-class antifungal drugs

Resistance to echinocandin-class antifungal drugs

Polissacarídeos de parede celular fúngica: purificação e caracterização

Nuevos antifúngicos: Las equinocandinas

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