TY  - JOUR
A1  - Schröder, Wiebke
A1  - Bernhardt, Jörg
A1  - Marincola, Gabriella
A1  - Klein-Hitpass, Ludger
A1  - Herbig, Alexander
A1  - Krupp, Guido
A1  - Nieselt, Kay
A1  - Wolz, Christiane
T1  - Altering gene expression by aminocoumarins: the role of DNA supercoiling in Staphylococcus aureus
JF  - BMC Genomics
N2  - BACKGROUND:
It has been shown previously that aminocoumarin antibiotics such as novobiocin lead to immediate downregulation of recA expression and thereby inhibit the SOS response, mutation frequency and recombination capacity in Staphylococcus aureus. Aminocoumarins function by inhibiting the ATPase activity of DNA gyrase subunit B with a severe impact on DNA supercoiling.
RESULTS:
Here, we have analysed the global impact of the DNA relaxing agent novobiocin on gene expression in S. aureus. Using a novobiocin-resistant mutant, it became evident that the change in recA expression is due to gyrase inhibition. Microarray analysis and northern blot hybridisation revealed that the expression levels of a distinct set of genes were increased (e.g., recF-gyrB-gyrA, the rib operon and the ure operon) or decreased (e.g., arlRS, recA, lukA, hlgC and fnbA) by novobiocin. The two-component ArlRS system was previously found to decrease the level of supercoiling in S. aureus. Thus, downregulation of arlRS might partially compensate for the relaxing effect of novobiocin. Global analysis and gene mapping of supercoiling-sensitive genes did not provide any indication that they are clustered in the genome. Promoter fusion assays confirmed that the responsiveness of a given gene is intrinsic to the promoter region but independent of the chromosomal location.
CONCLUSIONS:
The results indicate that the molecular properties of a given promoter, rather than the chromosomal topology, dictate the responsiveness to changes in supercoiling in the pathogen Staphylococcus aureus.
KW  - aminocoumarins
KW  - novobiocin
KW  - microarray
KW  - Voronoi tree map
KW  - spacer
KW  - arlR
KW  - gyrase
KW  - supercoiling
KW  - staphylococcus aureus
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-121609
SN  - 1471-2164
VL  - 15
IS  - 291
ER  - 
TY  - JOUR
A1  - Zhang, Nan
A1  - Van Crombruggen, Koen
A1  - Holtappels, Gabriele
A1  - Lan, Feng
A1  - Katotomichelakis, Michail
A1  - Zhang, Luo
A1  - Högger, Petra
A1  - Bachert, Claus
T1  - Suppression of Cytokine Release by Fluticasone Furoate vs. Mometasone Furoate in Human Nasal Tissue Ex-Vivo
JF  - PLOS ONE
N2  - Background: Topical glucocorticosteroids are the first line therapy for airway inflammation. Modern compounds with higher efficacy have been developed, but head-to-head comparison studies are sparse. 
Objective: To compare the activity of two intranasal glucocorticoids, fluticasone furoate (FF) and mometasone furoate (MF) with respect to the inhibition of T helper (Th)1, Th2 and Th17 cytokine release in airway mucosa. 
Methods: We used an ex-vivo human nasal mucosal tissue model and employed pre-and post-Staphylococcus aureus enterotoxin B (SEB)-challenge incubations with various time intervals and drug concentrations to mimic typical clinical situations of preventive or therapeutic use. 
Results: At a fixed concentration of 10(-10) M, FF had significantly higher suppressive effects on interferon (IFN)-gamma,interleukin (IL)-2 and IL-17 release, but not IL-5 or tumor necrosis factor (TNF)-alpha, vs. MF. While the maximal suppressive activity was maintained when FF was added before or after tissue stimulation, the cytokine suppression capacity of MF appeared to be compromised when SEB-induced cell activation preceded the addition of the drug. In a pre-challenge incubation setting with removal of excess drug concentrations, MF approached inhibition of IL-5 and TNF-alpha after 6 and 24 hours while FF maximally blocked the release of these cytokines right after pre-incubation. Furthermore, FF suppressed a wider range of T helper cytokines compared to MF. 
Conclusion: The study demonstrates the potential of our human mucosal model and shows marked differences in the ability to suppress the release of various cytokines in pre-and post-challenge settings between FF and MF mimicking typical clinical situations of preventive or therapeutic use.
KW  - allergic rhinitis
KW  - human receptor kinetics
KW  - staphylococcus aureus
KW  - intranasal corticosteroids
KW  - cells
KW  - propionate
KW  - secretion
KW  - affinity
KW  - therapy
KW  - spray
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-116779
VL  - 9
IS  - 4
ER  -