Cryptococcus neoformans: A Molecular Model for the Study of Fungal Pathogenesis and Drug Discovery in the Genomic Era

2003 ◽  
pp. 197-214
Author(s):  
Jennifer K. Lodge ◽  
John R. Perfect
Keyword(s):  
Drug Discovery ◽  
Cryptococcus Neoformans ◽  
Molecular Model ◽  
Fungal Pathogenesis

scholarly journals СИНТЕЗ ТА ДОСЛІДЖЕННЯ АНТИМІКРОБНОЇ АКТИВНОСТІ ДЕЯКИХ ПІРАЗОЛЗАМІЩЕНИХ 7H-[1,2,4]ТРИАЗОЛО[3,4-B][1,3,4]ТІАДІАЗИНІВ

2021 ◽  
pp. 5-13
Author(s):  
I. I. Myrko ◽  
T. I. Chaban ◽  
V. V. Ogurtsov ◽  
V. S. Matiychuk
Keyword(s):  
Escherichia Coli ◽  
Staphylococcus Aureus ◽  
Pseudomonas Aeruginosa ◽  
Candida Albicans ◽  
Drug Discovery ◽  
Klebsiella Pneumoniae ◽  
Acinetobacter Baumannii ◽  
Cryptococcus Neoformans ◽  
Antimicrobial Drug

Мета роботи. Здійснити синтез деяких нових піразолзаміщених 7H-[1,2,4]триазоло[3,4-b][1,3,4]тіадіазинів та провести дослідження антимікробних властивостей синтезованих сполук. Матеріали і методи. Органічний синтез, ЯМР-спектроскопія, елементний аналіз, фармакологічний скринінг. Результати й обговорення. У результаті взаємодії eтил (2Z)-хлоро(фенілгідразоно)ацетатів з ацетилацетоном було отримано етил 4-ацетил-5-метил-1-феніл-1H-піразол-3-карбоксилати. Зазначені сполуки піддали бромуванню, що дозволило одержати цільові бромкетони. Синтезовані на даній стадії етил 1-арил-4-(бромацетил)-5-метил-1Н-піразол-3-карбоксилати було введено у взаємодію з 4-аміно-5-арил(гетарил)-2,4-дигідро-3Н-1,2,4-триазол-3-тіонами з подальшим формуванням 1,3,4-тіадіазольного циклу та отриманням відповідних етил 1-арил-4-{3-арил(гетарил)-7H-[1,2,4]триазоло[3,4-b][1,3,4]тіадіазин-6-іл)}-5-метил-1H-піразол-3-карбоксилатів. Структура синтезованих сполук підтверджена даними елементного аналізу та ЯМР спектроскопією. В рамках міжнародного проекту "The Community for Antimicrobial Drug Discovery" (CO-ADD) за підтримки Wellcome Trust (Великобританія) і університету Квінсленда (Австралія) для синтезованих сполук здійснено скринінг антимікробної активності. Як тестові мікроорганізми використовували п'ять штамів бактерій: Escherichia coli ATCC 25922, Klebsiella pneumoniae ATCC 700603, Acinetobacter baumannii ATCC 19606, Pseudomonas aeruginosa ATCC 27853, Staphylococcus aureus ATCC 43300 та двох штамів грибків: Candida albicans ATCC 90028 і Cryptococcus neoformans ATCC 208821. Встановлено, що досліджувані сполуки виявляють різноманітну дію, від практично повної її відсутності до виразного антимікробного ефекту. Висновки. Здійснено синтез 12 нових етил 1-арил-4-{3-арил(гетарил)-7H-[1,2,4]триазоло[3,4-b][1,3,4]тіадіазин-6-іл)}-5-метил-1H-піразол-3-карбоксилатів. Зазначені речовини отримані шляхом взаємодії відповідних етил 1-арил-4-(бромацетил)-5-метил-1Н-піразол-3-карбоксилатів з 4-аміно-5-арил(гетарил)-2,4-дигідро-3Н-1,2,4-триазол-3-тіонами. Дослідження антимікробної активності синтезованих сполук демонструють потенціал пошуку антимікробних агентів серед зазначеного класу сполук.

scholarly journals A Unique α-1,3 Mannosyltransferase of the Pathogenic Fungus Cryptococcus neoformans

1999 ◽  
Vol 181 (17) ◽  
pp. 5482-5488 ◽  
Author(s):  
Tamara L. Doering
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Drug Discovery ◽  
Cryptococcus Neoformans ◽  
Glucuronic Acid ◽  
Divalent Cations ◽  
Pathogenic Fungus ◽  
Product Formation ◽  
Ph Optimum ◽  
Major Virulence Factor

ABSTRACT The major virulence factor of the pathogenic fungusCryptococcus neoformans is an extensive polysaccharide capsule which surrounds the cell. Almost 90% of the capsule is composed of a partially acetylated linear α-1,3-linked mannan substituted with d-xylose and d-glucuronic acid. A novel mannosyltransferase with specificity appropriate for a role in the synthesis of this glucuronoxylomannan is active in cryptococcal membranes. This membrane-associated activity transfers mannose in vitro from GDP-mannose to an α-1,3-dimannoside acceptor, forming a second α-1,3 linkage. Product formation by the transferase is dependent on protein, time, temperature, divalent cations, and each substrate. It is not affected by amphomycin or tunicamycin but is inhibited by GDP and mannose-1-phosphate. The described activity is not detectable in the model yeast Saccharomyces cerevisiae, consistent with the absence of a similar polysaccharide structure in that organism. A second mannosyltransferase from C. neoformans membranes adds mannose in α-1,2 linkage to the same dimannoside acceptor. The two activities differ in pH optimum and cation preference. While the α-1,2 transferase does not have specificity appropriate for a role in glucuronoxylomannan synthesis, it may participate in production of mannoprotein components of the capsule. This study suggests two new targets for antifungal drug discovery.

scholarly journals Cryptococcus neoformansCda1 and Its Chitin Deacetylase Activity Are Required for Fungal Pathogenesis

mBio ◽  
2018 ◽  
Vol 9 (6) ◽  
Author(s):  
Rajendra Upadhya ◽  
Lorina G. Baker ◽  
Woei C. Lam ◽  
Charles A. Specht ◽  
Maureen J. Donlin ◽  
...  
Keyword(s):  
Cell Wall ◽  
Cryptococcus Neoformans ◽  
Fungal Pathogenesis ◽  
Mammalian Host ◽  
Infection Model ◽  
Chitin Deacetylase ◽  
Fungal Cell ◽  
Content Type ◽  
Mutant Strains

ABSTRACTChitin is an essential component of the cell wall ofCryptococcus neoformansconferring structural rigidity and integrity under diverse environmental conditions. Chitin deacetylase genes encode the enyzmes (chitin deacetylases [Cdas]) that deacetylate chitin, converting it to chitosan. The functional role of chitosan in the fungal cell wall is not well defined, but it is an important virulence determinant ofC. neoformans. Mutant strains deficient in chitosan are completely avirulent in a mouse pulmonary infection model.C. neoformanscarries genes that encode three Cdas (Cda1, Cda2, and Cda3) that appear to be functionally redundant in cells grown under vegetative conditions. Here we report thatC. neoformansCda1 is the principal Cda responsible for fungal pathogenesis. Point mutations were introduced in the active site of Cda1 to generate strains in which the enzyme activity of Cda1 was abolished without perturbing either its stability or localization. When used to infect CBA/J mice, Cda1 mutant strains produced less chitosan and were attenuated for virulence. We further demonstrate thatC. neoformansCda genes are transcribed differently during a murine infection from what has been measuredin vitro.IMPORTANCECryptococcus neoformansis unique among fungal pathogens that cause disease in a mammalian host, as it secretes a polysaccharide capsule that hinders recognition by the host to facilitate its survival and proliferation. Even though it causes serious infections in immunocompromised hosts, reports of infection in hosts that are immunocompetent are on the rise. The cell wall of a fungal pathogen, its synthesis, composition, and pathways of remodelling are attractive therapeutic targets for the development of fungicides. Chitosan, a polysaccharide in the cell wall ofC. neoformansis one such target, as it is critical for pathogenesis and absent in the host. The results we present shed light on the importance of one of the chitin deacetylases that synthesize chitosan during infection and further implicates chitosan as being a critical factor for the pathogenesis ofC. neoformans.

scholarly journals Binding of the wheat germ lectin to Cryptococcus neoformans chitooligomers affects multiple mechanisms required for fungal pathogenesis

2013 ◽  
Vol 60 ◽  
pp. 64-73 ◽  
Author(s):  
Fernanda L. Fonseca ◽  
Allan J. Guimarães ◽  
Lívia Kmetzsch ◽  
Fabianno F. Dutra ◽  
Fernanda D. Silva ◽  
...  
Keyword(s):  
Cryptococcus Neoformans ◽  
Wheat Germ ◽  
Fungal Pathogenesis ◽  
Wheat Germ Lectin

Toward an alignment of the actin molecule within the actin filament

1983 ◽  
Vol 41 ◽  
pp. 450-451
Author(s):  
P.R. Smith ◽  
W.E. Fowler ◽  
U. Aebi
Keyword(s):  
Actin Filament ◽  
Diffraction Data ◽  
Quantitative Estimate ◽  
Molecular Model ◽  
Quantitative Comparison ◽  
Regulatory Proteins ◽  
Essential Information ◽  
X Ray ◽  
Maximum Resolution ◽  
Lack Of Information

An understanding of the specific interactions of actin with regulatory proteins has been limited by the lack of information about the structure of the actin filament. Molecular actin has been studied in actin-DNase I complexes by single crystal X-ray analysis, to a resolution of about 0.6nm, and in the electron microscope where two dimensional actin sheets have been reconstructed to a maximum resolution of 1.5nm. While these studies have shown something of the structure of individual actin molecules, essential information about the orientation of actin in the filament is still unavailable.The work of Egelman & DeRosier has, however, suggested a method which could be used to provide an initial quantitative estimate of the orientation of actin within the filament. This method involves the quantitative comparison of computed diffraction data from single actin filaments with diffraction data derived from synthetic filaments constructed using the molecular model of actin as a building block. Their preliminary work was conducted using a model consisting of two juxtaposed spheres of equal size.

Exploration of cell wall architecture with the rapid-freeze deep-etch technique

1993 ◽  
Vol 51 ◽  
pp. 128-129
Author(s):  
Béatrice Satiat-Jeunemaitre ◽  
Chris Hawes
Keyword(s):  
Plant Cell ◽  
Cell Walls ◽  
Cell Biology ◽  
Molecular Model ◽  
Three Dimensional ◽  
Secretory Activity ◽  
Wall Structure ◽  
Specimen Preparation ◽  
Molecular Architecture ◽  
Plant Cell Walls

The comprehension of the molecular architecture of plant cell walls is one of the best examples in cell biology which illustrates how developments in microscopy have extended the frontiers of a topic. Indeed from the first electron microscope observation of cell walls it has become apparent that our understanding of wall structure has advanced hand in hand with improvements in the technology of specimen preparation for electron microscopy. Cell walls are sub-cellular compartments outside the peripheral plasma membrane, the construction of which depends on a complex cellular biosynthetic and secretory activity (1). They are composed of interwoven polymers, synthesised independently, which together perform a number of varied functions. Biochemical studies have provided us with much data on the varied molecular composition of plant cell walls. However, the detailed intermolecular relationships and the three dimensional arrangement of the polymers in situ remains a mystery. The difficulty in establishing a general molecular model for plant cell walls is also complicated by the vast diversity in wall composition among plant species.

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