scholarly journals Synthesis and Physicochemical Characterization of Novel Dicyclopropyl-Thiazole Compounds as Nontoxic and Promising Antifungals

Materials ◽  
2021 ◽  
Vol 14 (13) ◽  
pp. 3500
Author(s):  
Anna Biernasiuk ◽  
Anna Banasiewicz ◽  
Maciej Masłyk ◽  
Aleksandra Martyna ◽  
Monika Janeczko ◽  
...  
Keyword(s):  
Cell Wall ◽  
Metabolic Activity ◽  
Mode Of Action ◽  
Physicochemical Characterization ◽  
Lung Fibroblasts ◽  
Wall Structure ◽  
Tetrazolium Salt ◽  
Antibiofilm Activity ◽  
Fungal Cell

There is a need to search for new antifungals, especially for the treatment of the invasive Candida infections, caused mainly by C. albicans. These infections are steadily increasing at an alarming rate, mostly among immunocompromised patients. The newly synthesized compounds (3a–3k) were characterized by physicochemical parameters and investigated for antimicrobial activity using the microdilution broth method to estimate minimal inhibitory concentration (MIC). Additionally, their antibiofilm activity and mode of action together with the effect on the membrane permeability in C. albicans were investigated. Biofilm biomass and its metabolic activity were quantitatively measured using crystal violet (CV) staining and tetrazolium salt (XTT) reduction assay. The cytotoxic effect on normal human lung fibroblasts and haemolytic effect were also evaluated. The results showed differential activity of the compounds against yeasts (MIC = 0.24–500 µg/mL) and bacteria (MIC = 125–1000 µg/mL). Most compounds possessed strong antifungal activity (MIC = 0.24–7.81 µg/mL). The compounds 3b, 3c and 3e, showed no inhibitory (at 1/2 × MIC) and eradication (at 8 × MIC) effect on C. albicans biofilm. Only slight decrease in the biofilm metabolic activity was observed for compound 3b. Moreover, the studied compounds increased the permeability of the membrane/cell wall of C. albicans and their mode of action may be related to action within the fungal cell wall structure and/or within the cell membrane. It is worth noting that the compounds had no cytotoxicity effect on pulmonary fibroblasts and erythrocytes at concentrations showing anticandidal activity. The present studies in vitro confirm that these derivatives appear to be a very promising group of antifungals for further preclinical studies.

scholarly journals Evaluation of Antifungal Activity and Mode of Action of New Coumarin Derivative, 7-Hydroxy-6-nitro-2H-1-benzopyran-2-one, againstAspergillusspp.

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Felipe Queiroga Sarmento Guerra ◽  
Rodrigo Santos Aquino de Araújo ◽  
Janiere Pereira de Sousa ◽  
Fillipe de Oliveira Pereira ◽  
Francisco J. B. Mendonça-Junior ◽  
...  
Keyword(s):  
Cell Wall ◽  
Mode Of Action ◽  
Cell Walls ◽  
Coumarin Derivative ◽  
Antifungal Drugs ◽  
Azole Resistance ◽  
Subinhibitory Concentration ◽  
Fungal Cell ◽  
Mycelia Growth

Aspergillusspp. produce a wide variety of diseases. For the treatment of such infections, the azoles and Amphotericin B are used in various formulations. The treatment of fungal diseases is often ineffective, because of increases in azole resistance and their several associated adverse effects. To overcome these problems, natural products and their derivatives are interesting alternatives. The aim of this study was to examine the effects of coumarin derivative, 7-hydroxy-6-nitro-2H-1-benzopyran-2-one (Cou-NO2), both alone and with antifungal drugs. Its mode of action againstAspergillusspp. Cou-NO2was tested to evaluate its effects on mycelia growth and germination of fungal conidia ofAspergillusspp. We also investigated possible Cou-NO2action on cell walls (0.8 M sorbitol) and on Cou-NO2to ergosterol binding in the cell membrane. The study shows that Cou-NO2is capable of inhibiting both the mycelia growth and germination of conidia for the species tested, and that its action affects the structure of the fungal cell wall. At subinhibitory concentration, Cou-NO2enhanced thein vitroeffects of azoles. Moreover, in combination with azoles (voriconazole and itraconazole) Cou-NO2displays an additive effect. Thus, our study supports the use of coumarin derivative 7-hydroxy-6-nitro-2H-1-benzopyran-2-one as an antifungal agent againstAspergillusspecies.

scholarly journals Biosynthesis of β-(1→5)-Galactofuranosyl Chains of Fungal-Type and O-Mannose-Type Galactomannans within the Invasive Pathogen Aspergillus fumigatus

2019 ◽  
Author(s):  
Yuria Chihara ◽  
Yutaka Tanaka ◽  
Minoru Izumi ◽  
Daisuke Hagiwara ◽  
Akira Watanabe ◽  
...  
Keyword(s):  
Cell Wall ◽  
Cell Surface ◽  
Aspergillus Fumigatus ◽  
Pathogenic Fungus ◽  
Cell Surface Hydrophobicity ◽  
Surface Hydrophobicity ◽  
Wall Structure ◽  
Fungal Cell ◽  
Animal Pathogens

ABSTRACTThe pathogenic fungus Aspergillus fumigatus contains galactomannans localized on the surface layer of its cell walls, which are involved in various biological processes. Galactomannans comprise α-(1→2)-/α-(1→6)-mannan and β-(1→5)-/β-(1→6)-galactofuranosyl chains. We previously revealed that GfsA is a β-galactofuranoside β-(1→5)-galactofuranosyltransferase involved in the biosynthesis of β-(1→5)-galactofuranosyl chains. Here, we clarified the entire biosynthesis of β-(1→5)-galactofuranosyl chains in A. fumigatgus. Two paralogs exist within A. fumigatus: GfsB and GfsC. We show that GfsB and GfsC, in addition to GfsA, are β-galactofuranoside β-(1→5)-galactofuranosyltransferases by biochemical and genetic analyses. GfsA, GfsB, and GfsC can synthesize β-(1→5)-galactofuranosyl oligomers up to lengths of 7, 3, and 5 galactofuranoses within an established in vitro highly efficient assay of galactofuranosyltransferase activity. Structural analyses of galactomannans extracted from the strains ΔgfsB, ΔgfsC, ΔgfsAC, and ΔgfsABC revealed that GfsA and GfsC synthesized all β-(1→5)-galactofuranosyl residues of fungal-type and O-mannose-type galactomannans, and GfsB exhibited limited function in A. fumigatus. The loss of β-(1→5)-galactofuranosyl residues decreased the hyphal growth rate and conidia formation ability as well as increased the abnormal hyphal branching structure and cell surface hydrophobicity, but this loss is dispensable for sensitivity to antifungal agents and virulence toward immune-compromised mice.IMPORTANCEβ-(1→5)-galactofuranosyl residues are widely distributed in the subphylum Pezisomycotina of the phylum Ascomycota. Pezizomycotina includes many plant and animal pathogens. Although the structure of β-(1→5)-galactofuranosyl residues of galactomannans in filamentous fungi was discovered long ago, it remains unclear which enzyme is responsible for biosynthesis of this glycan. Fungal cell wall formation processes are complicated, and information concerning glycosyltransferases is essential for their understanding. In this study, we show that GfsA and GfsC are responsible for the biosynthesis of all β-(1→5)-galactofuranosyl residues of fungal-type and O-mannose-type galactomannans. The data presented here indicates that β-(1→5)-galactofuranosyl residues are involved in cell growth, conidiation, polarity, and cell surface hydrophobicity. Our new understanding of β-(1→5)-galactofuranosyl residue biosynthesis provides important novel insights into the formation of the complex cell wall structure and the virulence of the subphylum Pezisomycotina.

scholarly journals The newly synthesized thiazole derivatives as potential antifungal compounds against Candida albicans

2021 ◽  
Author(s):  
Anna Biernasiuk ◽  
Anna Berecka-Rycerz ◽  
Anna Gumieniczek ◽  
Maria Malm ◽  
Krzysztof Z. Łączkowski ◽  
...  
Keyword(s):  
Cell Wall ◽  
Candida Albicans ◽  
Antifungal Activity ◽  
Cell Membrane ◽  
Mode Of Action ◽  
Thiazole Derivatives ◽  
Fungal Cell ◽  
Erythrocyte Lysis ◽  
Low Cytotoxicity ◽  
High Antifungal Activity

Abstract Recently, the occurrence of candidiasis has increased dramatically, especially in immunocompromised patients. Additionally, their treatment is often ineffective due to the resistance of yeasts to antimycotics. Therefore, there is a need to search for new antifungals. A series of nine newly synthesized thiazole derivatives containing the cyclopropane system, showing promising activity against Candida spp., has been further investigated. We decided to verify their antifungal activity towards clinical Candida albicans isolated from the oral cavity of patients with hematological malignancies and investigate the mode of action on fungal cell, the effect of combination with the selected antimycotics, toxicity to erythrocytes, and lipophilicity. These studies were performed by the broth microdilution method, test with sorbitol and ergosterol, checkerboard technique, erythrocyte lysis assay, and reversed phase thin-layer chromatography, respectively. All derivatives showed very strong activity (similar and even higher than nystatin) against all C. albicans isolates with minimal inhibitory concentration (MIC) = 0.008–7.81 µg/mL Their mechanism of action may be related to action within the fungal cell wall structure and/or within the cell membrane. The interactions between the derivatives and the selected antimycotics (nystatin, chlorhexidine, and thymol) showed additive effect only in the case of combination some of them and thymol. The erythrocyte lysis assay confirmed the low cytotoxicity of these compounds as compared to nystatin. The high lipophilicity of the derivatives was related with their high antifungal activity. The present studies confirm that the studied thiazole derivatives containing the cyclopropane system appear to be a very promising group of compounds in treatment of infections caused by C. albicans. However, this requires further studies in vivo. Key points • The newly thiazoles showed high antifungal activity and some of them — additive effect in combination with thymol. • Their mode of action may be related with the influence on the structure of the fungal cell wall and/or the cell membrane. • The low cytotoxicity against erythrocytes and high lipophilicity of these derivatives are their additional good properties. Graphical abstract

scholarly journals Synthesis of Biotin-Tagged Chitosan Oligosaccharides and Assessment of Their Immunomodulatory Activity

2020 ◽  
Vol 8 ◽  
Author(s):  
Yury E. Tsvetkov ◽  
Ema Paulovičová ◽  
Lucia Paulovičová ◽  
Pavol Farkaš ◽  
Nikolay E. Nifantiev
Keyword(s):  
Cell Wall ◽  
Chain Elongation ◽  
High Yield ◽  
Raw 264.7 Cells ◽  
Immunomodulatory Activity ◽  
Raw 264.7 ◽  
Fungal Cell ◽  
Chitosan Oligosaccharides ◽  
Chitin And Chitosan

Chitin, a polymer of β-(1→4)-linked N-acetyl-d-glucosamine, is one of the main polysaccharide components of the fungal cell wall. Its N-deacetylated form, chitosan, is enzymatically produced in the cell wall by chitin deacetylases. It exerts immunomodulative, anti-inflammatory, anti-cancer, anti-bacterial, and anti-fungal activities with various medical applications. To study the immunobiological properties of chitosan oligosaccharides, we synthesized a series of β-(1→4)-linked N-acetyl-d-glucosamine oligomers comprising 3, 5, and 7 monosaccharide units equipped with biotin tags. The key synthetic intermediate employed for oligosaccharide chain elongation, a disaccharide thioglycoside, was prepared by orthogonal glycosylation of a 4-OH thioglycoside acceptor with a glycosyl trichloroacetimidate bearing the temporary 4-O-tert-butyldimethylsilyl group. The use of silyl protection suppressed aglycon transfer and provided a high yield for the target disaccharide donor. Using synthesized chitosan oligomers, as well as previously obtained chitin counterparts, the immunobiological relationship between these synthetic oligosaccharides and RAW 264.7 cells was studied in vitro. Evaluation of cell proliferation, phagocytosis, respiratory burst, and Th1, Th2, Th17, and Treg polarized cytokine expression demonstrated effective immune responsiveness and immunomodulation in RAW 264.7 cells exposed to chitin- and chitosan-derived oligosaccharides. Macrophage reactivity was accompanied by significant inductive dose- and structure-dependent protective Th1 and Th17 polarization, which was greater with exposure to chitosan- rather than chitin-derived oligosaccharides. Moreover, no antiproliferative or cytotoxic effects were observed, even following prolonged 48 h exposure. The obtained results demonstrate the potent immunobiological activity of these synthetically prepared chito-oligosaccharides.

scholarly journals In vitro and in vivo reactivity to fungal cell wall agents in sarcoidosis

2011 ◽  
Vol 166 (1) ◽  
pp. 87-93 ◽  
Author(s):  
M. Terčelj ◽  
S. Stopinšek ◽  
A. Ihan ◽  
B. Salobir ◽  
S. Simčič ◽  
...  
Keyword(s):  
Cell Wall ◽  
Fungal Cell Wall ◽  
Fungal Cell

scholarly journals Up against the Wall: Is Yeast Cell Wall Integrity Ensured by Mechanosensing in Plasma Membrane Microdomains?

2014 ◽  
Vol 81 (3) ◽  
pp. 806-811 ◽  
Author(s):  
Christian Kock ◽  
Yves F. Dufrêne ◽  
Jürgen J. Heinisch
Keyword(s):  
Cell Wall ◽  
Plasma Membrane ◽  
Yeast Cell ◽  
Antifungal Drugs ◽  
Cell Wall Integrity ◽  
Yeast Cell Wall ◽  
Membrane Microdomains ◽  
Wall Structure ◽  
Fungal Cell ◽  
Membrane Spanning

ABSTRACTYeast cell wall integrity (CWI) signaling serves as a model of the regulation of fungal cell wall synthesis and provides the basis for the development of antifungal drugs. A set of five membrane-spanning sensors (Wsc1 to Wsc3, Mid2, and Mtl1) detect cell surface stress and commence the signaling pathway upon perturbations of either the cell wall structure or the plasma membrane. We here summarize the latest advances in the structure/function relationship primarily of the Wsc1 sensor and critically review the evidence that it acts as a mechanosensor. The relevance and physiological significance of the information obtained for the function of the other CWI sensors, as well as expected future developments, are discussed.

Cell wall alterations in staphylococci growing in situ in experimental osteomyelitis

1987 ◽  
Vol 33 (2) ◽  
pp. 142-150 ◽  
Author(s):  
J. W. Costerton ◽  
D. W. Lambe Jr. ◽  
K.-J. Mayberry-Carson ◽  
B. Tober-Meyer
Keyword(s):  
Cell Wall ◽  
Cell Size ◽  
Wall Structure ◽  
Specific Cell ◽  
Experimental Osteomyelitis ◽  
Rich Media ◽  
Rabbit Tibia ◽  
Rabbit Bone

When cells of both Staphylococcus aureus and Staphylococcus epidermidis are grown in batch culture in nutrient-rich media, their cell walls are regular in thickness, their cell size is within the normal range for each species, and their septation patterns are orderly. When cells of each of these species are examined directly in infected tissue in the rabbit tibia model infection, their cell wall thickness is often much increased and very irregular around the circumference of the cell, their cell size is often increased, and their septation patterns are often severely deranged. All of these alterations in cell wall structure occur in the absence of antibiotics, and we suggest that they may be an expression of phenotypic plasticity in response to altered environmental conditions such as specific nutrient limitations, the presence of antibacterial factors, and growth of the cells on hard surfaces such as rabbit bone or plastic catheters. Some of these specific cell wall alterations are also seen when staphylococcal cells are exposed, in vitro or in vivo, to antibiotics such as clindamycin, but we emphasize that growth in tissue alone is sufficient for their induction.

scholarly journals Human Antibodies against a Purified Glucosylceramide from Cryptococcus neoformans Inhibit Cell Budding and Fungal Growth

2000 ◽  
Vol 68 (12) ◽  
pp. 7049-7060 ◽  
Author(s):  
Marcio L. Rodrigues ◽  
Luiz R. Travassos ◽  
Kildare R. Miranda ◽  
Anderson J. Franzen ◽  
Sonia Rozental ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Cell Wall ◽  
Cryptococcus Neoformans ◽  
High Performance ◽  
Fungal Growth ◽  
Fungal Cell ◽  
Human Antibodies ◽  
Different Strains ◽  
Immunofluorescence Labeling

ABSTRACT A major ceramide monohexoside (CMH) was purified from lipidic extracts of Cryptococcus neoformans. This molecule was analyzed by high-performance thin-layer chromatography (HPTLC), gas chromatography coupled with mass spectrometry, and fast atom bombardment-mass spectrometry. The cryptococcal CMH is a β-glucosylceramide, with the carbohydrate residue attached to 9-methyl-4,8-sphingadienine in amidic linkage to 2-hydroxyoctadecanoic acid. Sera from patients with cryptococcosis and a few other mycoses reacted with the cryptococcal CMH. Specific antibodies were purified from patients' sera by immunoadsorption on the purified glycolipid followed by protein G affinity chromatography. The purified antibodies to CMH (mainly immunoglobulin G1) bound to different strains and serological types of C. neoformans, as shown by flow cytofluorimetry and immunofluorescence labeling. Transmission electron microscopy of yeasts labeled with immunogold-antibodies to CMH and immunostaining of isolated cell wall lipid extracts separated by HPTLC showed that the cryptococcal CMH predominantly localizes to the fungal cell wall. Confocal microscopy revealed that the β-glucosylceramide accumulates mostly at the budding sites of dividing cells with a more disperse distribution at the cell surface of nondividing cells. The increased density of sphingolipid molecules seems to correlate with thickening of the cell wall, hence with its biosynthesis. The addition of human antibodies to CMH to cryptococcal cultures of both acapsular and encapsulated strains of C. neoformans inhibited cell budding and cell growth. This process was complement-independent and reversible upon removal of the antibodies. The present data suggest that the cryptococcal β-glucosylceramide is a fungal antigen that plays a role on the cell wall synthesis and yeast budding and that antibodies raised against this component are inhibitory in vitro.

scholarly journals A Review on Microorganisms-Derived Products as Potential Antimicrobial Agents

2021 ◽  
Author(s):  
Alka Rani ◽  
Khem Chand Saini ◽  
Felix Bast ◽  
Sunita Varjani ◽  
Sanjeet Mehariya ◽  
...  
Keyword(s):  
Cell Wall ◽  
Antimicrobial Peptides ◽  
Bioactive Compounds ◽  
Mode Of Action ◽  
Antimicrobial Agents ◽  
State Of The Art ◽  
Drug Resistant ◽  
Fungal Cell ◽  
Glucan Synthase ◽  
Streptomyces Sp

Microorganisms including actinomycetes, archaea, bacteria, fungi, yeast, and micro algae are the auspicious source of vital bioactive compounds. In this review, the existing state of the art re-garding antimicrobial molecules from microorganisms has been summarized. The potential an-timicrobial compounds from actinomycetes, particularly Streptomyces sp.; archaea; fungi including endophytic and marine-derived fungi, mushroom; yeast, and microalgae were briefly described. Furthermore, this review briefly summarized the activity and mode of action of bacteriocins, a ribosomally synthesized antimicrobial peptides product of Eurotium sp., Streptomyces parvulus, S. thermophiles, Lactococcus lactis, etc. Bacteriocins have inherent properties such as targeting multi-ple-drug resistant pathogens, which allows them to be considered next-generation antibiotics. Similarly, Glarea lozoyensis derived antifungal lipohexpeptides i.e., pneumocandins, inhibits 1,3-β-glucan synthase of the fungal cell wall and acts as a precursor for the synthesis of caspo-fungin, is also elaborated. In conclusion, this review highlights the possibility of using microor-ganisms as an antimicrobial resource for biotechnological, nutraceutical, and pharmaceutical ap-plications. However, more investigations are still required to separate, purify, and characterize these bioactive compounds and transfer these primary drugs into clinically approved antibiotics.

scholarly journals Staphylococcus aureus cell wall structure and dynamics during host-pathogen interaction

2021 ◽  
Vol 17 (3) ◽  
pp. e1009468
Author(s):  
Joshua A. F. Sutton ◽  
Oliver T. Carnell ◽  
Lucia Lafage ◽  
Joe Gray ◽  
Jacob Biboy ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Cell Wall ◽  
Cell Walls ◽  
Ex Vivo ◽  
Cell Wall Structure ◽  
Wall Structure ◽  
Bacterial Cells ◽  
Human Macrophages ◽  
Structure And Dynamics

Peptidoglycan is the major structural component of the Staphylococcus aureus cell wall, in which it maintains cellular integrity, is the interface with the host, and its synthesis is targeted by some of the most crucial antibiotics developed. Despite this importance, and the wealth of data from in vitro studies, we do not understand the structure and dynamics of peptidoglycan during infection. In this study we have developed methods to harvest bacteria from an active infection in order to purify cell walls for biochemical analysis ex vivo. Isolated ex vivo bacterial cells are smaller than those actively growing in vitro, with thickened cell walls and reduced peptidoglycan crosslinking, similar to that of stationary phase cells. These features suggested a role for specific peptidoglycan homeostatic mechanisms in disease. As S. aureus penicillin binding protein 4 (PBP4) has reduced peptidoglycan crosslinking in vitro its role during infection was established. Loss of PBP4 resulted in an increased recovery of S. aureus from the livers of infected mice, which correlated with enhanced fitness within murine and human macrophages. Thicker cell walls correlate with reduced activity of peptidoglycan hydrolases. S. aureus has a family of 4 putative glucosaminidases, that are collectively crucial for growth. Loss of the major enzyme SagB, led to attenuation during murine infection and reduced survival in human macrophages. However, loss of the other three enzymes Atl, SagA and ScaH resulted in clustering dependent attenuation, in a zebrafish embryo, but not a murine, model of infection. A combination of pbp4 and sagB deficiencies resulted in a restoration of parental virulence. Our results, demonstrate the importance of appropriate cell wall structure and dynamics during pathogenesis, providing new insight to the mechanisms of disease.

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