TY  - JOUR
A1  - Hennessen, Fabienne
A1  - Miethke, Marcus
A1  - Zaburannyi, Nestor
A1  - Loose, Maria
A1  - Lukežič, Tadeja
A1  - Bernecker, Steffen
A1  - Hüttel, Stephan
A1  - Jansen, Rolf
A1  - Schmiedel, Judith
A1  - Fritzenwanker, Moritz
A1  - Imirzalioglu, Can
A1  - Vogel, Jörg
A1  - Westermann, Alexander J.
A1  - Hesterkamp, Thomas
A1  - Stadler, Marc
A1  - Wagenlehner, Florian
A1  - Petković, Hrvoje
A1  - Herrmann, Jennifer
A1  - Müller, Rolf
T1  - Amidochelocardin overcomes resistance mechanisms exerted on tetracyclines and natural chelocardin
JF  - Antibiotics
N2  - The reassessment of known but neglected natural compounds is a vital strategy for providing novel lead structures urgently needed to overcome antimicrobial resistance. Scaffolds with resistance-breaking properties represent the most promising candidates for a successful translation into future therapeutics. Our study focuses on chelocardin, a member of the atypical tetracyclines, and its bioengineered derivative amidochelocardin, both showing broad-spectrum antibacterial activity within the ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) panel. Further lead development of chelocardins requires extensive biological and chemical profiling to achieve favorable pharmaceutical properties and efficacy. This study shows that both molecules possess resistance-breaking properties enabling the escape from most common tetracycline resistance mechanisms. Further, we show that these compounds are potent candidates for treatment of urinary tract infections due to their in vitro activity against a large panel of multidrug-resistant uropathogenic clinical isolates. In addition, the mechanism of resistance to natural chelocardin was identified as relying on efflux processes, both in the chelocardin producer Amycolatopsis sulphurea and in the pathogen Klebsiella pneumoniae. Resistance development in Klebsiella led primarily to mutations in ramR, causing increased expression of the acrAB-tolC efflux pump. Most importantly, amidochelocardin overcomes this resistance mechanism, revealing not only the improved activity profile but also superior resistance-breaking properties of this novel antibacterial compound.
KW  - chelocardins
KW  - atypical tetracyclines
KW  - broad-spectrum antibiotics
KW  - clinical isolates
KW  - uropathogens
KW  - urinary tract infection (UTI)
KW  - resistance-breaking properties
KW  - mechanism of resistance
KW  - AcrAB-TolC efflux pump
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-213149
SN  - 2079-6382
VL  - 9
IS  - 9
ER  - 
TY  - JOUR
A1  - Müller, Anna A.
A1  - Dolowschiak, Tamas
A1  - Sellin, Mikael E.
A1  - Felmy, Boas
A1  - Verbree, Carolin
A1  - Gadient, Sandra
A1  - Westermann, Alexander J.
A1  - Vogel, Jörg
A1  - LeibundGut-Landmann, Salome
A1  - Hardt, Wolf-Dietrich
T1  - An NK Cell Perforin Response Elicited via IL-18 Controls Mucosal Inflammation Kinetics during Salmonella Gut Infection
JF  - PLoS Pathogens
N2  - Salmonella Typhimurium (S.Tm) is a common cause of self-limiting diarrhea. The mucosal inflammation is thought to arise from a standoff between the pathogen's virulence factors and the host's mucosal innate immune defenses, particularly the mucosal NAIP/NLRC4 inflammasome. However, it had remained unclear how this switches the gut from homeostasis to inflammation. This was studied using the streptomycin mouse model. S.Tm infections in knockout mice, cytokine inhibition and –injection experiments revealed that caspase-1 (not -11) dependent IL-18 is pivotal for inducing acute inflammation. IL-18 boosted NK cell chemoattractants and enhanced the NK cells' migratory capacity, thus promoting mucosal accumulation of mature, activated NK cells. NK cell depletion and Prf\(^{-/-}\) ablation (but not granulocyte-depletion or T-cell deficiency) delayed tissue inflammation. Our data suggest an NK cell perforin response as one limiting factor in mounting gut mucosal inflammation. Thus, IL-18-elicited NK cell perforin responses seem to be critical for coordinating mucosal inflammation during early infection, when S.Tm strongly relies on virulence factors detectable by the inflammasome. This may have broad relevance for mucosal defense against microbial pathogens.
KW  - NK cells
KW  - Salmonella Typhimurium
KW  - mucosal inflammation
KW  - diarrhea
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-167429
VL  - 12
IS  - 6
ER  -