scholarly journals Systems impact of zinc chelation by the epipolythiodioxopiperazine dithiol gliotoxin in Aspergillus fumigatus: a new direction in natural product functionality

Metallomics ◽  
2018 ◽  
Vol 10 (6) ◽  
pp. 854-866 ◽  
Author(s):  
Aliabbas A. Saleh ◽  
Gary W. Jones ◽  
Frances C. Tinley ◽  
Stephen F. Delaney ◽  
Sahar H. Alabbadi ◽  
...  
Keyword(s):  
Aspergillus Fumigatus ◽  
Natural Product ◽  
Multiple Impacts ◽  
Zinc Chelator ◽  
Zinc Chelation ◽  
Product Functionality

Dithiol gliotoxin (DTG) is a zinc chelator and an inability to dissipate DTG in Aspergillus fumigatus is associated with multiple impacts which are linked to zinc chelation.

scholarly journals Administration of Zinc Chelators Improves Survival of Mice Infected with Aspergillus fumigatus both in Monotherapy and in Combination with Caspofungin

2016 ◽  
Vol 60 (10) ◽  
pp. 5631-5639 ◽  
Author(s):  
Paris Laskaris ◽  
Ahmad Atrouni ◽  
José Antonio Calera ◽  
Christophe d'Enfert ◽  
Hélène Munier-Lehmann ◽  
...  
Keyword(s):  
Aspergillus Fumigatus ◽  
Treatment Options ◽  
Intraperitoneal Administration ◽  
Fungal Growth ◽  
Content Type ◽  
Improvement In Survival ◽  
Zinc Chelation ◽  
Immunosuppressed Mice ◽  
Host Tissues

ABSTRACTAspergillus fumigatuscan infect immunocompromised patients, leading to high mortality rates due to the lack of reliable treatment options. This pathogen requires uptake of zinc from host tissues in order to successfully grow and cause virulence. Reducing the availability of that micronutrient could help treatA. fumigatusinfections. In this study, we examined thein vitroeffects of seven chelators using a bioluminescent strain ofA. fumigatus. 1,10-Phenanthroline andN,N,N′,N′-tetrakis(2-pyridylmethyl)ethane-1,2-diamine (TPEN) proved to be the chelators most effective at inhibiting fungal growth. Intraperitoneal administration of either phenanthroline or TPEN resulted in a significant improvement in survival and decrease of weight loss and fungal burden for immunosuppressed mice intranasally infected withA. fumigatus.In vitroboth chelators had an indifferent effect when employed in combination with caspofungin. The use of TPEN in combination with caspofungin also significantly increased survival compared to that when using these drugs individually. Our results suggest that zinc chelation may be a valid strategy for dealing withA. fumigatusinfections and that both phenanthroline and TPEN could potentially be used either independently or in combination with caspofungin, indicating that their use in combination with other antifungal treatments might also be applicable.

Ruakuric acid: A natural product from Aspergillus fumigatus

1996 ◽  
Vol 43 (1) ◽  
pp. 209-214 ◽  
Author(s):  
Horace G. Cutler ◽  
Denis R. Lauren ◽  
Alistair L. Wilkins ◽  
Patrick T. Holland ◽  
Robert A. Hill ◽  
...  
Keyword(s):  
Aspergillus Fumigatus ◽  
Natural Product

scholarly journals Calprotectin-mediated zinc chelation inhibits Pseudomonas aeruginosa protease activity in cystic fibrosis sputum

2021 ◽  
Author(s):  
Danielle M. Vermilyea ◽  
Alex W. Crocker ◽  
Alex H. Gifford ◽  
Deborah A. Hogan
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Metal Binding ◽  
Large Fraction ◽  
Starvation Response ◽  
Variable Activity ◽  
Zinc Chelator ◽  
Zinc Levels ◽  
Zinc Chelation

Pseudomonas aeruginosa induces pathways indicative of low zinc availability in the cystic fibrosis (CF) lung environment. To learn more about P. aeruginosa zinc access in CF, we grew P. aeruginosa strain PAO1 directly in expectorated CF sputum. The P. aeruginosa Zur transcriptional repressor controls the response to low intracellular zinc, and we used the NanoString methodology to monitor levels of Zur-regulated transcripts including those encoding a zincophore system, a zinc importer, and paralogs of zinc containing proteins that do not require zinc for activity. Zur-controlled transcripts were induced in sputum-grown P. aeruginosa compared to control cultures, but not if the sputum was amended with zinc. Amendment of sputum with ferrous iron did not reduce expression of Zur-regulated genes. A reporter fusion to a Zur-regulated promoter had variable activity in P. aeruginosa grown in sputum from different donors, and this variation inversely correlated with sputum zinc concentrations. Recombinant human calprotectin (CP), a divalent-metal binding protein released by neutrophils, was sufficient to induce a zinc-starvation response in P. aeruginosa grown in laboratory medium or zinc-amended CF sputum indicating that CP is functional in the sputum environment. Zinc metalloproteases comprise a large fraction of secreted zinc-binding P. aeruginosa proteins. Here we show that recombinant CP inhibited both LasB-mediated casein degradation and LasA-mediated lysis of Staphylococcus aureus, which was reversible with added zinc. These studies reveal the potential for CP-mediated zinc chelation to post-translationally inhibit zinc metalloprotease activity and thereby impact the protease-dependent physiology and/or virulence of P. aeruginosa in the CF lung environment. Importance The factors that contribute to worse outcomes in individuals with cystic fibrosis (CF) with chronic Pseudomonas aeruginosa infections are not well understood. Therefore, there is a need to understand environmental factors within the CF airway that contribute to P. aeruginosa colonization and infection. We demonstrate that growing bacteria in CF sputum induces a zinc-starvation response that inversely correlates with sputum zinc levels. Additionally, both calprotectin and a chemical zinc chelator inhibit the proteolytic activities of LasA and LasB proteases suggesting that extracellular zinc chelators can influence proteolytic activity and thus P. aeruginosa virulence and nutrient acquisition in vivo.

ChemInform Abstract: Ruakuric Acid: A Natural Product from Aspergillus fumigatus.

ChemInform ◽  
2010 ◽  
Vol 27 (48) ◽  
pp. no-no
Author(s):  
H. G. CUTLER ◽  
D. R. LAUREN ◽  
A. L. WILKINS ◽  
P. T. HOLLAND ◽  
R. A. HILL ◽  
...  
Keyword(s):  
Aspergillus Fumigatus ◽  
Natural Product

Synthetic studies toward inducamide C

2021 ◽  
Author(s):  
Ardalan A. Nabi ◽  
Lydia M. Scott ◽  
Daniel P. Furkert ◽  
Jonathan Sperry
Keyword(s):  
Natural Product ◽  
Structural Revision ◽  
Synthetic Studies

The rare benzoxazepine ring in the alkaloid inducamide C is unstable and prone to rearrangement, indicating that structural revision of the natural product may be necessary.

Lessons learned from the optimization of natural product based kinase inhibitors through molecular calculations

Planta Medica ◽  
2008 ◽  
Vol 74 (09) ◽  
Author(s):  
V Myrianthopoulos ◽  
P Magiatis ◽  
AL Skaltsounis ◽  
L Meijer ◽  
E Mikros
Keyword(s):  
Natural Product ◽  
Kinase Inhibitors ◽  
Lessons Learned ◽  
Molecular Calculations
Sign in / Sign up

Export Citation Format

Share Document