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Fungal cell wall inhibitor

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
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 also required for extracellular matrix generation by animal cells. Herein, we provide evidence for a uridine diphospho-N-acetylglucosamine (UDP-GlcNAc) pathway in Pneumocystis species. Using in silico search of the P...
September 15, 2016: American Journal of Respiratory Cell and Molecular Biology
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
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
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...
2016: BMC Microbiology
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
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
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...
June 3, 2016: Journal of Basic Microbiology
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
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
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
Paul A Mann, Catherine A McLellan, Sandra Koseoglu, Qian Si, Elena Kuzmin, Amy Flattery, Guy Harris, Xinwei Sher, Nicholas Murgolo, Hao Wang, Kristine Devito, Nuria de Pedro, Olga Genilloud, Jennifer Nielsen Kahn, Bo Jiang, Michael Costanzo, Charlie Boone, Charles G Garlisi, Susan Lindquist, Terry Roemer
Steadily increasing antifungal drug resistance and persistent high rates of fungal-associated mortality highlight the dire need for the development of novel antifungals. Characterization of inhibitors of one enzyme in the GPI anchor pathway, Gwt1, has generated interest in the exploration of targets in this pathway for further study. Utilizing a chemical genomics-based screening platform referred to as the Candida albicans fitness test (CaFT), we have identified novel inhibitors of Gwt1 and a second enzyme in the glycosylphosphatidylinositol (GPI) cell wall anchor pathway, Mcd4...
January 9, 2015: ACS Infectious Diseases
Kristína Kováčová, Vladimír Farkaš
Polysaccharide endotransglycosylases (PETs) are the cell wall-modifying enzymes of fungi and plants. They catalyze random endo-splitting of the polysaccharide donor molecule and transfer of the newly formed reducing sugar residue to the nonreducing end of an acceptor molecule which can be a polysaccharide or an oligosaccharide. Owing to their important role in the cell wall formation, the inhibition of PETs represents an attractive strategy in the fight against fungal infections. We have elaborated two variants of a versatile high-throughput microplate fluorimetric assay that could be used for effective identification of PETs and screening of their inhibitors...
April 2016: Applied Biochemistry and Biotechnology
Humberto H Lara, Dulce G Romero-Urbina, Christopher Pierce, Jose L Lopez-Ribot, M Josefina Arellano-Jiménez, Miguel Jose-Yacaman
BACKGROUND: Candida albicans is the most common pathogenic fungus isolated in bloodstream infections in hospitalized patients, and candidiasis represents the fourth most common infection in United States hospitals, mostly due to the increasing numbers of immune- and medically-compromised patients. C. albicans has the ability to form biofilms and morphogenetic conversions between yeast and hyphal morphologies contribute to biofilm development and represent an essential virulence factor...
December 15, 2015: Journal of Nanobiotechnology
F Courjol, C Mille, R A Hall, A Masset, R Aijjou, N A R Gow, D Poulain, T Jouault, C Fradin
Pathogenic and non-pathogenic fungi synthesize glycosphingolipids, which have a crucial role in growth and viability. Glycosphingolipids also contribute to fungal-associated pathogenesis. The opportunistic yeast pathogen Candida albicans synthesizes phospholipomannan (PLM), which is a glycosphingolipid of the mannosylinositol phosphorylceramide family. Through its lipid and glycan moieties, PLM contributes to the initial recognition of the yeast, causing immune system disorder and persistent fungal disease through activation of host signaling pathways...
January 2016: Biochimie
Ye Liu, Na Liu, Yanni Yin, Yun Chen, Jinhua Jiang, Zhonghua Ma
Histone H3 lysine 4 methylation (H3K4me) is generally associated with actively transcribed genes in a variety of eukaryotes. The function of H3K4me in phytopathogenic fungi remains unclear. Here, we report that FgSet1 is predominantly responsible for mono-, di- and trimethylation of H3K4 in Fusarium graminearum. The FgSET1 deletion mutant (ΔFgSet1) was crippled in hyphal growth and virulence. H3K4me is required for the active transcription of genes involved in deoxynivalenol and aurofusarin biosyntheses. Unexpectedly, FgSet1 plays an important role in the response of F...
November 2015: Environmental Microbiology
Tina J Penn, Mark E Wood, Darren M Soanes, Michael Csukai, Andrew John Corran, Nicholas J Talbot
Protein kinase C constitutes a family of serine-threonine kinases found in all eukaryotes and implicated in a wide range of cellular functions, including regulation of cell growth, cellular differentiation and immunity. Here, we present three independent lines of evidence which indicate that protein kinase C is essential for viability of Magnaporthe oryzae. First, all attempts to generate a target deletion of PKC1, the single copy protein kinase C-encoding gene, proved unsuccessful. Secondly, conditional gene silencing of PKC1 by RNA interference led to severely reduced growth of the fungus, which was reversed by targeted deletion of the Dicer2-encoding gene, MDL2...
October 2015: Molecular Microbiology
Nathalia R Moreira, Christiane Cardoso, Alberto F Ribeiro, Clelia Ferreira, Walter R Terra
α-Mannosidases are enzymes which remove non-reducing terminal residues from glycoconjugates. Data on both GH47 and GH38 (Golgi and lysosomal) enzymes are available. Data on insect midgut α-mannosidases acting in digestion are preliminary and do not include enzyme sequences. Tenebrio molitor midgut α-mannosidases were separated by chromatography into two activity peaks: a major (Man1) and a minor (Man2). An antibody generated against a synthetic peptide corresponding to a sequence of α-mannosidase fragment recognizes Man2 but not Man1...
December 2015: Insect Biochemistry and Molecular Biology
Vineeta Singh, Vandana Praveen, Divya Tripathi, Shafiul Haque, Pallavi Somvanshi, S B Katti, C K M Tripathi
During the search for a potent antifungal drug, a cell-permeable metabolite was isolated from a soil isolate taxonomically identified as Penicillium radicum. The strain was found to be a potent antifungal agent. Production conditions of the active compound were optimized and the active compound was isolated, purified, characterized and identified as a phosphoinositide 3-kinase (PI3K) inhibitor, commonly known as wortmannin (Wtmn). This is very first time we are reporting the production of Wtmn from P. radicum...
2015: Scientific Reports
Gabriel Mircus, Nathaniel Albert, Dafna Ben-Yaakov, Dodo Chikvashvili, Yona Shadkchan, Dimitrios P Kontoyiannis, Nir Osherov
Invasive mycotic infections have become more common during recent decades, posing an increasing threat to public health. However, despite the growing needs, treatments for invasive fungal infections remain unsatisfactory and are limited to a small number of antifungals. The aim of this study was to identify novel fungal cell wall inhibitors from a library of small chemical compounds using a conditional protein kinase C (PKC)-expressing strain of Aspergillus nidulans sensitive to cell wall-active agents. Eight "hit" compounds affecting cell wall integrity were identified from a screen of 35,000 small chemical compounds...
September 2015: Antimicrobial Agents and Chemotherapy
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