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Patent
Twincore GmbH and Cnrs | Date: 2013-03-22

The present invention relates to flavone derivatives and to compositions containing one or more of these flavone derivatives. The present invention further relates to flavone derivatives or compositions for use in the treatment and/or prevention of a viral infection, and to a method of preventing or treating these infections.


Haussler S.,TWINCORE GmbH | Haussler S.,Helmholtz Center for Infection Research | Blanka A.,TWINCORE GmbH | VanHook A.M.,Science Signaling
Science Signaling | Year: 2015

This Podcast features an interview with Andrea Blanka and Susanne Häussler, authors of a Research Article that appears in the 14 April 2015 issue of Science Signaling, about a mutation that enhances the ability of a pathogenic strain of Pseudomonas aeruginosa to form biofilms. Biofilms are microbial communities that grow on biological and nonbiological surfaces. The microbes in biofilms are embedded in a complex matrix that protects them from antibiotics and from being destroyed by the immune system. P. aeruginosa is an opportunistic pathogen that is more difficult to treat when it forms a biofilm than when it exists as freeliving cells. Variants of P. aeruginosa that have an enhanced ability to form biofilms are frequently isolated from the chronically infected lungs of cystic fibrosis (CF) patients. Blanka et al. identified a mutation in a strain of CFassociated P. aeruginosa that affects lipid metabolism, leading to altered composition of the bacterial plasma membrane. This mutation caused the bacteria to constitutively produce the second messenger cdiGMP, which promotes biofilm formation. Source


Ahmad I.,Karolinska Institutet | Wigren E.,Karolinska Institutet | Le Guyon S.,Karolinska Institutet | Vekkeli S.,Karolinska Institutet | And 11 more authors.
Molecular Microbiology | Year: 2013

Summary: The ubiquitous second messenger c-di-GMP regulates the switching of bacterial lifestyles from motility to sessility and acute to chronic virulence to adjust bacterial fitness to altered environmental conditions. Conventionally, EAL proteins being c-di-GMP phosphodiesterases promote motility and acute virulence phenotypes such as invasion into epithelial cells and inhibit biofilm formation. We report here that in contradiction, the EAL-like protein STM1697 of Salmonella typhimurium suppresses motility, invasion into HT-29 epithelial cell line and secretion of the type three secretion system 1 effector protein SipA, whereas it promotes rdar biofilm formation and CsgD expression. STM1697 can, however, functionally replace the EAL-like protein STM1344 and vice versa, whereby both proteins neither degrade nor bind c-di-GMP. Like STM1344, STM1697 suppresses the transcription of class 2 and class 3 flagella regulon genes by binding to FlhD, a component of the master regulator of the flagella regulon FlhD4C2 and act additively under numerous conditions. Interestingly, the interaction interface of STM1697 with FlhD2 is distinct from its paralogue STM1344. We predict that the stand alone EAL domain proteins STM1697 and STM1344 belong to a subclass of EAL domain proteins in S.typhimurium, which are all involved in motility, biofilm and virulence regulation through interaction with proteins that regulate flagella function. © 2013 John Wiley & Sons Ltd. Source


Khaledi A.,Helmholtz Center for Infection Research | Khaledi A.,TWINCORE GmbH | Schniederjans M.,Helmholtz Center for Infection Research | Schniederjans M.,TWINCORE GmbH | And 18 more authors.
Antimicrobial Agents and Chemotherapy | Year: 2016

Emerging resistance to antimicrobials and the lack of new antibiotic drug candidates underscore the need for optimization of current diagnostics and therapies to diminish the evolution and spread of multidrug resistance. As the antibiotic resistance status of a bacterial pathogen is defined by its genome, resistance profiling by applying next-generation sequencing (NGS) technologies may in the future accomplish pathogen identification, prompt initiation of targeted individualized treatment, and the implementation of optimized infection control measures. In this study, qualitative RNA sequencing was used to identify key genetic determinants of antibiotic resistance in 135 clinical Pseudomonas aeruginosa isolates from diverse geographic and infection site origins. By applying transcriptome-wide association studies, adaptive variations associated with resistance to the antibiotic classes fluoroquinolones, aminoglycosides, and β-lactams were identified. Besides potential novel biomarkers with a direct correlation to resistance, global patterns of phenotype-associated gene expression and sequence variations were identified by predictive machine learning approaches. Our research serves to establish genotype-based molecular diagnostic tools for the identification of the current resistance profiles of bacterial pathogens and paves the way for faster diagnostics for more efficient, targeted treatment strategies to also mitigate the future potential for resistance evolution. Copyright © 2016, American Society for Microbiology. All Rights Reserved. Source


Blanka A.,TWINCORE GmbH | Schulz S.,TWINCORE GmbH | Schulz S.,Helmholtz Center for Infection Research | Eckweiler D.,TWINCORE GmbH | And 12 more authors.
Journal of Bacteriology | Year: 2014

Pseudomonas aeruginosa is distinguished by its broad metabolic diversity and its remarkable capability for adaptation, which relies on a large collection of transcriptional regulators and alternative sigma (σ) factors. The largest group of alternative σ factors is that of the extracytoplasmic function (ECF) σ factors, which control key transduction pathways for maintenance of envelope homeostasis in response to external stress and cell growth. In addition, there are specific roles of alternative σ factors in regulating the expression of virulence and virulence-associated genes. Here, we analyzed a deletion mutant of the ECF σ factor SigX and applied mRNA profiling to define the SigX-dependent regulon in P. aeruginosa in response to low-osmolarity-medium conditions. Furthermore, the combination of transcriptional data with chromatin immunoprecipitation (ChIP) followed by high-throughput sequencing (ChIP-seq) led to the identification of the DNA binding motif of SigX. Genome-wide mapping of SigX-binding regions revealed enrichment of downstream genes involved in fatty acid biosynthesis, type III secretion, swarming and cyclic di-GMP (c-di-GMP) signaling. In accordance, a sigX deletion mutant exhibited altered fatty acid composition of the cell membrane, reduced cytotoxicity, impaired swarming activity, elevated c-di-GMP levels, and increased biofilm formation. In conclusion, a combination of ChIP-seq with transcriptional profiling and bioinformatic approaches to define consensus DNA binding sequences proved to be effective for the elucidation of the regulon of the alternative σ factor SigX, revealing its role in complex virulence-associated phenotypes in P. aeruginosa. © 2014, American Society for Microbiology. Source

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