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Fungal cell wall inhibitor

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https://www.readbyqxmd.com/read/28611248/the-aspergillus-fumigatus-crza-transcription-factor-activates-chitin-synthase-gene-expression-during-the-caspofungin-paradoxical-effect
#1
Laure Nicolas Annick Ries, Marina Campos Rocha, Patrícia Alves de Castro, Rafael Silva-Rocha, Roberto Nascimento Silva, Fernanda Zanolli Freitas, Leandro José de Assis, Maria Célia Bertolini, Iran Malavazi, Gustavo H Goldman
Aspergillus fumigatus is an opportunistic fungal pathogen that causes invasive aspergillosis (IA), a life-threatening disease in immunocompromised humans. The echinocandin caspofungin, adopted as a second-line therapy in combating IA, is a β-1,3-glucan synthase inhibitor, which, when used in high concentrations, reverts the anticipated A. fumigatus growth inhibition, a phenomenon called the "caspofungin paradoxical effect" (CPE). The CPE has been widely associated with increased chitin content in the cell wall due to a compensatory upregulation of chitin synthase-encoding genes...
June 13, 2017: MBio
https://www.readbyqxmd.com/read/28579986/hiv-aspartic-peptidase-inhibitors-modulate-surface-molecules-and-enzyme-activities-involved-with-physiopathological-events-in-fonsecaea-pedrosoi
#2
Vanila F Palmeira, Daniela S Alviano, Lys A Braga-Silva, Fátima R V Goulart, Marcela Q Granato, Sonia Rozental, Celuta S Alviano, André L S Santos, Lucimar F Kneipp
Fonsecaea pedrosoi is the main etiological agent of chromoblastomycosis, a recalcitrant disease that is extremely difficult to treat. Therefore, new chemotherapeutics to combat this fungal infection are urgently needed. Although aspartic peptidase inhibitors (PIs) currently used in the treatment of human immunodeficiency virus (HIV) have shown anti-F. pedrosoi activity their exact mechanisms of action have not been elucidated. In the present study, we have investigated the effects of four HIV-PIs on crucial virulence attributes expressed by F...
2017: Frontiers in Microbiology
https://www.readbyqxmd.com/read/28469160/differential-roles-for-six-p-type-calcium-atpases-in-sustaining-intracellular-ca-2-homeostasis-asexual-cycle-and-environmental-fitness-of-beauveria-bassiana
#3
Jie Wang, Xiao-Guan Zhu, Sheng-Hua Ying, Ming-Guang Feng
A global insight into the roles of multiple P-type calcium ATPase (CA) pumps in sustaining the life of a filamentous fungal pathogen is lacking. Here we elucidated the functions of five CA pumps (Eca1, Spf1 and PmcA/B/C) following previous characterization of Pmr1 in Beauveria bassiana, a fungal insect pathogen. The fungal CA pumps interacted at transcriptional level, at which singular deletions of five CA genes depressed eca1 expression by 76-98% and deletion of spf1 resulted in drastic upregulation of four CA genes by 36-50-fold...
May 3, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28250363/resistance-of-aspergillus-fumigatus-to-micafungin-is-increased-by-exogenous-%C3%AE-glucan
#4
Takashi Toyoshima, Ken-Ichi Ishibashi, Daisuke Yamanaka, Yoshiyuki Adachi, Naohito Ohno
Aspergillus species are ubiquitous in the environment and Aspergillus fumigatus can cause life-threatening infections in immunocompromised patients. β-1,3-/1,6-glucan is a major fungal cell wall polysaccharide that has various biological effects on the infected host, but little is known about the influence of β-glucan on the fungus itself. In a previous study, we demonstrated that the cell wall β-glucan content could be increased in Aspergillus spp. by addition of β-glucan to the culture medium. In this study, we investigated the influence of β-glucan on the susceptibility of A...
2017: Medical Mycology Journal
https://www.readbyqxmd.com/read/28137806/preclinical-pharmacokinetics-and-pharmacodynamic-target-of-scy-078-a-first-in-class-orally-active-antifungal-glucan-synthesis-inhibitor-in-murine-models-of-disseminated-candidiasis
#5
Stephen A Wring, Ryan Randolph, SeongHee Park, George Abruzzo, Qing Chen, Amy Flattery, Graig Garrett, Michael Peel, Russell Outcalt, Kendall Powell, Michelle Trucksis, David Angulo, Katyna Borroto-Esoda
SCY-078 (MK-3118) is a novel, semisynthetic derivative of enfumafungin and represents the first compound of the triterpene class of antifungals. SCY-078 exhibits potent inhibition of β-(1,3)-d-glucan synthesis, an essential cell wall component of many pathogenic fungi, including Candida spp. and Aspergillus spp. SCY-078 is currently in phase 2 clinical development for the treatment of invasive fungal diseases. In vitro disposition studies to assess solubility, intestinal permeability, and metabolic stability were predictive of good oral bioavailability...
April 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28119468/candida-albicans-chitin-increases-arginase-1-activity-in-human-macrophages-with-an-impact-on-macrophage-antimicrobial-functions
#6
Jeanette Wagener, Donna M MacCallum, Gordon D Brown, Neil A R Gow
The opportunistic human fungal pathogen Candida albicans can cause a variety of diseases, ranging from superficial mucosal infections to life-threatening systemic infections. Phagocytic cells of the innate immune response, such as neutrophils and macrophages, are important first-line responders to an infection and generate reactive oxygen and nitrogen species as part of their protective antimicrobial response. During an infection, host cells generate nitric oxide through the enzyme inducible nitric oxide synthase (iNOS) to kill the invading pathogen...
January 24, 2017: MBio
https://www.readbyqxmd.com/read/28079053/molecular-evidence-for-the-involvement-of-a-polygalacturonase-inhibiting-protein-ghpgip1-in-enhanced-resistance-to-verticillium-and-fusarium-wilts-in-cotton
#7
Nana Liu, Xueyan Zhang, Yun Sun, Ping Wang, Xiancai Li, Yakun Pei, Fuguang Li, Yuxia Hou
Polygalacturonase-inhibiting protein (PGIP), belonging to a group of plant defence proteins, specifically inhibits endopolygalacturonases secreted by pathogens. Herein, we showed that purified GhPGIP1 is a functional inhibitor of Verticillium dahliae and Fusarium oxysporum f. sp. vasinfectum, the two fungal pathogens causing cotton wilt. Transcription of GhPGIP1 was increased in cotton upon infection, wounding, and treatment with defence hormone and H2O2. Resistance by GhPGIP1 was examined by its virus-induced gene silencing in cotton and overexpression in Arabidopsis...
January 12, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28060864/a-major-facilitator-superfamily-transporter-mediated-resistance-to-oxidative-stress-and-fungicides-requires-yap1-skn7-and-map-kinases-in-the-citrus-fungal-pathogen-alternaria-alternata
#8
Li-Hung Chen, Hsieh-Chin Tsai, Pei-Ling Yu, Kuang-Ren Chung
Major Facilitator Superfamily (MFS) transporters play an important role in multidrug resistance in fungi. We report an AaMFS19 gene encoding a MFS transporter required for cellular resistance to oxidative stress and fungicides in the phytopathogenic fungus Alternaria alternata. AaMFS19, containing 12 transmembrane domains, displays activity toward a broad range of substrates. Fungal mutants lacking AaMFS19 display profound hypersensitivities to cumyl hydroperoxide, potassium superoxide, many singlet oxygen-generating compounds (eosin Y, rose Bengal, hematoporphyrin, methylene blue, and cercosporin), and the cell wall biosynthesis inhibitor, Congo red...
2017: PloS One
https://www.readbyqxmd.com/read/27859907/identification-and-functional-ascertainment-of-the-pneumocystis-jirovecii-potential-drug-targets-gsc1-and-kre6-involved-in-glucan-synthesis
#9
Amanda Luraschi, Ousmane H Cissé, Marco Pagni, Philippe M Hauser
The most efficient drug against the human pathogenic fungus Pneumocystis jirovecii is cotrimoxazole targeting the folate biosynthesis. However, resistance toward it is emerging and adverse effects occur in some patients. Studies in rodent models suggested that echinocandins could be useful to treat Pneumocystis pneumonia. Echinocandins inhibit the catalytic subunit Gsc1 of the enzymatic complex ensuring the synthesis of 1,3-β glucan, an essential constituent of cell walls of most fungi. Besides, inhibitors of the enzyme Kre6 involved in the synthesis of 1,6-β glucan, another essential component of fungal walls, were recently described...
November 17, 2016: Journal of Eukaryotic Microbiology
https://www.readbyqxmd.com/read/27695031/metal-chelation-as-a-powerful-strategy-to-probe-cellular-circuitry-governing-fungal-drug-resistance-and-morphogenesis
#10
Elizabeth J Polvi, Anna F Averette, Soo Chan Lee, Taeyup Kim, Yong-Sun Bahn, Amanda O Veri, Nicole Robbins, Joseph Heitman, Leah E Cowen
Fungal pathogens have evolved diverse strategies to sense host-relevant cues and coordinate cellular responses, which enable virulence and drug resistance. Defining circuitry controlling these traits opens new opportunities for chemical diversity in therapeutics, as the cognate inhibitors are rarely explored by conventional screening approaches. This has great potential to address the pressing need for new therapeutic strategies for invasive fungal infections, which have a staggering impact on human health...
October 2016: PLoS Genetics
https://www.readbyqxmd.com/read/27632412/characterization-of-n-acetylglucosamine-biosynthesis-in-pneumocystis-species-a-new-potential-target-for-therapy
#11
Theodore J Kottom, Deanne M Hebrink, Paige E Jenson, Jorge H Ramirez-Prado, Andrew H Limper
N-acetylglucosamine (GlcNAc) serves as an essential structural sugar on the cell surface of organisms. For example, GlcNAc is a major component of bacterial peptidoglycan, it is an important building block of fungal cell walls, including a major constituent of chitin and mannoproteins, and it is also required for extracellular matrix generation by animal cells. Herein, we provide evidence for a uridine diphospho (UDP)-GlcNAc pathway in Pneumocystis species. Using an in silico search of the Pneumocystis jirovecii and P...
February 2017: American Journal of Respiratory Cell and Molecular Biology
https://www.readbyqxmd.com/read/27449515/identification-of-genes-in-candida-glabrata-conferring-altered-responses-to-caspofungin-a-cell-wall-synthesis-inhibitor
#12
Anne G Rosenwald, Gaurav Arora, Rocco Ferrandino, Erica L Gerace, Maedeh Mohammednetej, Waseem Nosair, Shemona Rattila, Amanda Zirzow Subic, Ronda Rolfes
Candida glabrata is an important human fungal pathogen whose incidence continues to rise. Because many clinical isolates are resistant to azole drugs, the drugs of choice to treat such infections are members of the echinocandin family, although there are increasing reports of resistance to these drugs as well. In efforts to better understand the genetic changes that lead to altered responses to echinocandins, we screened a transposon-insertion library of mutants for strains to identify genes that are important for cellular responses to caspofungin, a member of this drug family...
2016: G3: Genes—Genomes—Genetics
https://www.readbyqxmd.com/read/27429875/in-silico-screening-for-identification-of-novel-%C3%AE-1-3-glucan-synthase-inhibitors-using-pharmacophore-and-3d-qsar-methodologies
#13
Potshangbam Angamba Meetei, R S Rathore, N Prakash Prabhu, Vaibhav Vindal
The enzyme β-1,3-glucan synthase, which catalyzes the synthesis of β-1,3-glucan, an essential and unique structural component of the fungal cell wall, has been considered as a promising target for the development of less toxic anti-fungal agents. In this study, a robust pharmacophore model was developed and structure activity relationship analysis of 42 pyridazinone derivatives as β-1,3-glucan synthase inhibitors were carried out. A five-point pharmacophore model, consisting of two aromatic rings (R) and three hydrogen bond acceptors (A) was generated...
2016: SpringerPlus
https://www.readbyqxmd.com/read/27405320/genomic-characterization-of-plant-cell-wall-degrading-enzymes-and-in-silico-analysis-of-xylanses-and-polygalacturonases-of-fusarium-virguliforme
#14
Hao-Xun Chang, Craig R Yendrek, Gustavo Caetano-Anolles, Glen L Hartman
BACKGROUND: Plant cell wall degrading enzymes (PCWDEs) are a subset of carbohydrate-active enzymes (CAZy) produced by plant pathogens to degrade plant cell walls. To counteract PCWDEs, plants release PCWDEs inhibitor proteins (PIPs) to reduce their impact. Several transgenic plants expressing exogenous PIPs that interact with fungal glycoside hydrolase (GH)11-type xylanases or GH28-type polygalacturonase (PG) have been shown to enhance disease resistance. However, many plant pathogenic Fusarium species were reported to escape PIPs inhibition...
July 12, 2016: BMC Microbiology
https://www.readbyqxmd.com/read/27303738/the-endoplasmic-reticulum-mitochondrion-tether-ermes-orchestrates-fungal-immune-evasion-illuminating-inflammasome-responses-to-hyphal-signals
#15
Timothy M Tucey, Jiyoti Verma-Gaur, Julie Nguyen, Victoria L Hewitt, Tricia L Lo, Miguel Shingu-Vazquez, Avril A B Robertson, James R Hill, Filomena A Pettolino, Travis Beddoe, Matthew A Cooper, Thomas Naderer, Ana Traven
The pathogenic yeast Candida albicans escapes macrophages by triggering NLRP3 inflammasome-dependent host cell death (pyroptosis). Pyroptosis is inflammatory and must be tightly regulated by host and microbe, but the mechanism is incompletely defined. We characterized the C. albicans endoplasmic reticulum (ER)-mitochondrion tether ERMES and show that the ERMES mmm1 mutant is severely crippled in killing macrophages despite hyphal formation and normal phagocytosis and survival. To understand dynamic inflammasome responses to Candida with high spatiotemporal resolution, we established live-cell imaging for parallel detection of inflammasome activation and pyroptosis at the single-cell level...
May 2016: MSphere
https://www.readbyqxmd.com/read/27303693/the-zinc-finger-protein-mig1-regulates-mitochondrial-function-and-azole-drug-susceptibility-in-the-pathogenic-fungus-cryptococcus-neoformans
#16
Mélissa Caza, Guanggan Hu, Michael Price, John R Perfect, James W Kronstad
The opportunistic pathogen Cryptococcus neoformans causes fungal meningoencephalitis in immunocompromised individuals. In previous studies, we found that the Hap complex in this pathogen represses genes encoding mitochondrial respiratory functions and tricarboxylic acid (TCA) cycle components under low-iron conditions. The orthologous Hap2/3/4/5 complex in Saccharomyces cerevisiae exerts a regulatory influence on mitochondrial functions, and Hap4 is subject to glucose repression via the carbon catabolite repressor Mig1...
January 2016: MSphere
https://www.readbyqxmd.com/read/27259000/cell-wall-composition-plays-a-key-role-on-sensitivity-of-filamentous-fungi-to-chitosan
#17
Almudena Aranda-Martinez, Federico Lopez-Moya, Luis Vicente Lopez-Llorca
Chitosan antifungal activity has been reported for both filamentous fungi and yeast. Previous studies have shown fungal plasma membrane as main chitosan target. However, the role of the fungal cell wall (CW) in their response to chitosan is unknown. We show that cell wall regeneration in Neurospora crassa (chitosan sensitive) protoplasts protects them from chitosan damage. Caspofungin, a β-1,3-glucan synthase inhibitor, showed a synergistic antifungal effect with chitosan for N. crassa but not for Pochonia chlamydosporia, a biocontrol fungus resistant to chitosan...
October 2016: Journal of Basic Microbiology
https://www.readbyqxmd.com/read/27191378/the-cek1%C3%A2-mediated-map-kinase-pathway-regulates-exposure-of-%C3%AE-%C3%A2-1-2-and-%C3%AE-%C3%A2-1-2%C3%A2-mannosides-in-the-cell-wall-of-candida-albicans-modulating-immune-recognition
#18
E Román, I Correia, A Salazin, C Fradin, T Jouault, D Poulain, F-T Liu, J Pla
The Cek1 MAP kinase (MAPK) mediates vegetative growth and cell wall biogenesis in the fungal pathogen Candida albicans. Alterations in the fungal cell wall caused by a defective Cek1‑mediated signaling pathway leads to increased β‑1,3‑glucan exposure influencing dectin‑1 fungal recognition by immune cells. We show here that cek1 cells also display an increased exposure of α‑1,2 and β‑1,2‑mannosides (α‑M and β‑M), a phenotype shared by strains defective in the activating MAPKK Hst7, suggesting a general defect in cell wall assembly...
July 3, 2016: Virulence
https://www.readbyqxmd.com/read/27014234/%C3%AE-24-sterol-methyltransferase-plays-an-important-role-in-the-growth-and-development-of-sporothrix-schenckii-and-sporothrix-brasiliensis
#19
Luana P Borba-Santos, Gonzalo Visbal, Thalita Gagini, Anderson M Rodrigues, Zoilo P de Camargo, Leila M Lopes-Bezerra, Kelly Ishida, Wanderley de Souza, Sonia Rozental
Inhibition of Δ(24)-sterol methyltransferase (24-SMT) in Sporothrix schenckii sensu stricto and Sporothrix brasiliensis was investigated in vitro. The effects on fungal growth and sterol composition of the 24-SMT inhibitor 22-hydrazone-imidazolin-2-yl-chol-5-ene-3β-ol (H3) were compared to those of itraconazole. MIC and MFC analysis showed that H3 was more effective than itraconazole against both species in both their filamentous and yeast forms. H3 showed fungistatic activity in a time-kill assay, with inhibitory activity stronger than that of itraconazole...
2016: Frontiers in Microbiology
https://www.readbyqxmd.com/read/26928395/exploring-the-plant-microbe-interface-by-profiling-the-surface-associated-proteins-of-barley-grains
#20
Abida Sultan, Birgit Andersen, Birte Svensson, Christine Finnie
Cereal grains are colonized by a microbial community that actively interacts with the plant via secretion of various enzymes, hormones, and metabolites. Microorganisms decompose plant tissues by a collection of depolymerizing enzymes, including β-1,4-xylanases, that are in turn inhibited by plant xylanase inhibitors. To gain insight into the importance of the microbial consortia and their interaction with barley grains, we used a combined gel-based (2-DE coupled to MALDI-TOF-TOF MS) and gel-free (LC-MS/MS) proteomics approach complemented with enzyme activity assays to profile the surface-associated proteins and xylanolytic activities of two barley cultivars...
April 1, 2016: Journal of Proteome Research
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