scholarly journals Damage to Aspergillus fumigatus and Rhizopus oryzae Hyphae by Oxidative and Nonoxidative Microbicidal Products of Human Neutrophils In Vitro

1982 ◽  
Vol 38 (2) ◽  
pp. 487-495 ◽  
Author(s):  
Richard D. Diamond ◽  
Robert A. Clark
Keyword(s):  
Aspergillus Fumigatus ◽  
Rhizopus Oryzae ◽  
Human Neutrophils

scholarly journals Synergy, Pharmacodynamics, and Time-Sequenced Ultrastructural Changes of the Interaction between Nikkomycin Z and the Echinocandin FK463 against Aspergillus fumigatus

2001 ◽  
Vol 45 (12) ◽  
pp. 3310-3321 ◽  
Author(s):  
Christine C. Chiou ◽  
Nikolaos Mavrogiorgos ◽  
Elizabeth Tillem ◽  
Richard Hector ◽  
Thomas J. Walsh
Keyword(s):  
Cell Wall ◽  
Aspergillus Fumigatus ◽  
Rhizopus Oryzae ◽  
Ultrastructural Changes ◽  
Synergistic Activity ◽  
Partial Recovery ◽  
Electron Microscopic ◽  
Wide Range ◽  
Nikkomycin Z

ABSTRACT We investigated the potential synergy between two cell wall-active agents, the echinocandin FK463 (FK) and the chitin synthase inhibitor nikkomycin Z (NZ), against 16 isolates of filamentous fungi. Susceptibility testing was performed with a broth macrodilution procedure by NCCLS methods. The median minimal effective concentration (MEC) of FK against all Aspergillus species was 0.25 μg/ml (range, 0.05 to 0.5 μg/ml). For Fusarium solaniand Rhizopus oryzae, MECs of FK were >512 μg/ml. The median MEC of NZ against Aspergillus fumigatus was 32 μg/ml (range, 8 to 64 μg/ml), and that against R. oryzae was 0.5 μg/ml (range, 0.06 to 2 μg/ml); however, for the other Aspergillus species, as well as F. solani, MECs were >512 μg/ml. A checkerboard inhibitory assay demonstrated synergy against A. fumigatus (median fractional inhibitory concentration index = 0.312 [range, 0.15 to 0.475]). The effect was additive to indifferent against R. oryzae and indifferent against other Aspergillus spp. and F. solani. We further investigated the pharmacodynamics of hyphal damage by MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay and examined the time-sequenced changes in hyphal ultrastructure. Significant synergistic hyphal damage was demonstrated with the combination of NZ (2 to 32 μg/ml) and FK (0.03 to 0.5 μg/ml) over a wide range of concentrations (P < 0.001). The synergistic effect was most pronounced after 12 h of incubation and was sustained through 24 h. Time-sequenced light and electron microscopic studies demonstrated that structural alterations of hyphae were profound, with marked transformation of hyphae to blastospore-like structures, in the presence of FK plus NZ, while fungi treated with a single drug showed partial recovery at 24 h. The methods used in this study may be applicable to elucidating the activity and interaction of other cell wall-active agents. In summary, these two cell wall-targeted antifungal agents, FK and NZ, showed marked time-dependent in vitro synergistic activity against A. fumigatus.

scholarly journals Analysis of the in vitro activity of human neutrophils against Aspergillus fumigatus in presence of antifungal and immunosuppressive agents

2017 ◽  
Vol 56 (4) ◽  
pp. 514-519 ◽  
Author(s):  
Christina Decker ◽  
Sebastian Wurster ◽  
Maria Lazariotou ◽  
Anna-Maria Hellmann ◽  
Hermann Einsele ◽  
...  
Keyword(s):  
Aspergillus Fumigatus ◽  
Immunosuppressive Agents ◽  
Vitro Activity ◽  
Human Neutrophils ◽  
In Vitro Activity

scholarly journals Gliotoxin Is a Virulence Factor of Aspergillus fumigatus: gliP Deletion Attenuates Virulence in Mice Immunosuppressed with Hydrocortisone

2007 ◽  
Vol 6 (9) ◽  
pp. 1562-1569 ◽  
Author(s):  
Janyce A. Sugui ◽  
Julian Pardo ◽  
Yun C. Chang ◽  
Kol A. Zarember ◽  
Glenn Nardone ◽  
...  
Keyword(s):  
Aspergillus Fumigatus ◽  
Virulence Factor ◽  
High Performance ◽  
Superoxide Production ◽  
In Vitro Assays ◽  
Mouse Strains ◽  
Human Neutrophils ◽  
Pathogenic Potential ◽  
Chromatography Analysis

ABSTRACT Gliotoxin is an immunosuppressive mycotoxin long suspected to be a potential virulence factor of Aspergillus fumigatus. Recent studies using mutants lacking gliotoxin production, however, suggested that the mycotoxin is not important for pathogenesis of A. fumigatus in neutropenic mice resulting from treatment with cyclophosphomide and hydrocortisone. In this study, we report on the pathobiological role of gliotoxin in two different mouse strains, 129/Sv and BALB/c, that were immunosuppressed by hydrocortisone alone to avoid neutropenia. These strains of mice were infected using the isogenic set of a wild type strain (B-5233) and its mutant strain (gliPΔ) and the the glip reconstituted strain (gliP R). The gliP gene encodes a nonribosomal peptide synthase that catalyzes the first step in gliotoxin biosynthesis. The gliPΔ strain was significantly less virulent than strain B-5233 or gliP R in both mouse models. In vitro assays with culture filtrates (CFs) of B-5233, gliPΔ, and gliP R strains showed the following: (i) deletion of gliP abrogated gliotoxin production, as determined by high-performance liquid chromatography analysis; (ii) unlike the CFs from strains B-5233 and gliP R, gliPΔ CFs failed to induce proapoptotic processes in EL4 thymoma cells, as tested by Bak conformational change, mitochondrial-membrane potential disruption, superoxide production, caspase 3 activation, and phosphatidylserine translocation. Furthermore, superoxide production in human neutrophils was strongly inhibited by CFs from strain B-5233 and the gliP R strain, but not the gliPΔ strain. Our study confirms that gliotoxin is an important virulence determinant of A. fumigatus and that the type of immunosuppression regimen used is important to reveal the pathogenic potential of gliotoxin.

scholarly journals Synthesis of Novel Benzylic 1,2,3-triazole-4-carboxamides and their in vitro Activity Against Clinically Common Fungal Species

2021 ◽  
Vol 65 (2) ◽  
Author(s):  
Davir González-Calderón ◽  
Ricardo García-Monroy ◽  
Alejandra Ramírez-Villalva ◽  
Salvador Mastachi-Loza ◽  
José G. Aguirre-de Paz ◽  
...  
Keyword(s):  
Aspergillus Fumigatus ◽  
Rhizopus Oryzae ◽  
Fungal Species ◽  
In Vitro Assays ◽  
Trichosporon Cutaneum ◽  
Mucor Hiemalis ◽  
One Pot ◽  
Reference Drug ◽  
Para Determinar

Abstract. A library of novel benzylic 1,2,3-triazole-4-carboxamides (3a-m) were obtained with acceptable yields via a one-pot procedure. The series of compounds was screened for fungicidal activity and evaluated in vitro against four filamentous fungi and four Candida species. The former consisted of Aspergillus fumigatus, Trichosporon cutaneum, Rhizopus oryzae and Mucor hiemalis, and the latter C. krusei, C. albicans, C. utilis and C. glabrata. According to the in vitro assays, 3d and 3e were the most efficient fungicidal agents (of all the test compounds) against R. oryzae, even better than the reference drug (itraconazole). Thus, 3d and 3e represent important scaffolds that can be modified to increase antifungal activity. Additionally, they are candidates for complementary studies on the inhibition of clinical infections produced by Rhizopus spp. strains.   Resumen. Se obtuvo una librería de nuevos bencil 1,2,3-triazoles-4-carboxamidas (3a-m) con rendimientos aceptables mediante un procedimiento one-pot. La serie de compuestos se seleccionó para determinar la actividad fungicida llevando a cabo una evaluación in vitro contra cuatro hongos filamentosos y cuatro especies de Candida. Los primeros consistieron en Aspergillus fumigatus, Trichosporon cutaneum, Rhizopus oryzae y Mucor hiemalis, mientras que para las segundas especies, esta fueron C. krusei, C. albicans, C. utilis y C. glabrata. Según los ensayos in vitro, 3d y 3e fueron los agentes fungicidas más eficaces (de todos los compuestos de prueba) contra R. oryzae, incluso mejores que el fármaco de referencia (itraconazol). Por tanto, 3d y 3e representan importantes núcleos que podrían modificarse para aumentar la actividad antifúngica, siendo excelentes candidatos para estudios complementarios sobre la inhibición de infecciones clínicas producidas por Rhizopus spp.

scholarly journals In Vitro and In Vivo Antifungal Profile of a Novel and Long-Acting Inhaled Azole, PC945, on Aspergillus fumigatus Infection

2017 ◽  
Vol 61 (5) ◽  
Author(s):  
Thomas Colley ◽  
Alexandre Alanio ◽  
Steven L. Kelly ◽  
Gurpreet Sehra ◽  
Yasuo Kizawa ◽  
...  
Keyword(s):  
Aspergillus Fumigatus ◽  
Rhizopus Oryzae ◽  
Pathogenic Fungi ◽  
Spectrophotometric Analysis ◽  
Characteristic Type ◽  
Content Type ◽  
Long Acting ◽  
Immunocompromised Mice

ABSTRACT The profile of PC945, a novel triazole antifungal designed for administration via inhalation, was assessed in a range of in vitro and in vivo studies. PC945 was characterized as a potent, tightly binding inhibitor of Aspergillus fumigatus sterol 14α-demethylase (CYP51A and CYP51B) activity (50% inhibitory concentrations [IC50s], 0.23 μM and 0.22 μM, respectively) with characteristic type II azole binding spectra. Against 96 clinically isolated A. fumigatus strains, the MIC values of PC945 ranged from 0.032 to >8 μg/ml, while those of voriconazole ranged from 0.064 to 4 μg/ml. Spectrophotometric analysis of the effects of PC945 against itraconazole-susceptible and -resistant A. fumigatus growth yielded IC50 (determined based on optical density [OD]) values of 0.0012 to 0.034 μg/ml, whereas voriconazole (0.019 to >1 μg/ml) was less effective than PC945. PC945 was effective against a broad spectrum of pathogenic fungi (with MICs ranging from 0.0078 to 2 μg/ml), including Aspergillus terreus, Trichophyton rubrum, Candida albicans, Candida glabrata, Candida krusei, Cryptococcus gattii, Cryptococcus neoformans, and Rhizopus oryzae (1 or 2 isolates each). In addition, when A. fumigatus hyphae or human bronchial cells were treated with PC945 and then washed, PC945 was found to be absorbed quickly into both target and nontarget cells and to produce persistent antifungal effects. Among temporarily neutropenic immunocompromised mice infected with A. fumigatus intranasally, 50% of the animals survived until day 7 when treated intranasally with PC945 at 0.56 μg/mouse, while posaconazole showed similar effects (44%) at 14 μg/mouse. This profile affirms that topical treatment with PC945 should provide potent antifungal activity in the lung.

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