A5075469040- Antibiotic Resistance in Bacteria
- Antimicrobial Peptides and Activities
- Bacterial biofilms and quorum sensing
- Computational Drug Discovery Methods
- Cancer therapeutics and mechanisms
- RNA and protein synthesis mechanisms
- Bacteriophages and microbial interactions
- Tuberculosis Research and Epidemiology
- Bacterial Genetics and Biotechnology
- Biochemical and Molecular Research
- Biochemical and Structural Characterization
- Click Chemistry and Applications
- Microbial Natural Products and Biosynthesis
- Drug Transport and Resistance Mechanisms
- Chemical Synthesis and Analysis
- HIV/AIDS drug development and treatment
- Pneumocystis jirovecii pneumonia detection and treatment
- Hormonal Regulation and Hypertension
- Peptidase Inhibition and Analysis
- Antimicrobial Resistance in Staphylococcus
- ATP Synthase and ATPases Research
- MicroRNA in disease regulation
- RNA Interference and Gene Delivery
- Inhalation and Respiratory Drug Delivery
- Carbohydrate Chemistry and Synthesis
Helmholtz Centre for Infection Research
2015-2025
Helmholtz Institute for Pharmaceutical Research Saarland
2016-2025
German Center for Infection Research
2025
Saarland University
2007-2024
Goethe University Frankfurt
2011-2013
University Hospital Frankfurt
2012-2013
Goethe Institute
2012
University Medical Center Hamburg-Eppendorf
2012
Universität Hamburg
2012
Research Institute of Human Morphology
2012
Abstract The ubiquitous opportunistic pathogen Pseudomonas aeruginosa is responsible for severe infections and notoriously known acquiring antimicrobial resistance. Inhibiting the bacterium's extracellular elastase, LasB – a zinc‐dependent protease presents promising strategy to mitigate its virulence. Within this medicinal chemistry–driven hit‐to‐lead optimization campaign, new series of highly potent dipeptidic phosphonates designed synthesized following structure–based drug‐discovery...
The liver contains large amounts of microRNA-122 (miR-122), whereas other tissues contain only marginal this miRNA. MicroRNAs have also been found to circulate in the blood a cell-free form; their potential as readily accessible disease markers is currently evaluated. Here, we investigated if serum levels miR-122 might be useful parameter patients with chronic hepatitis C virus (HCV) infection.RNA was extracted from sera HCV infection (CHC) and healthy controls analyzed for miR-22 content by...
Background MicroRNAs circulating in the blood, stabilized by complexation with proteins and/or additionally encapsulation lipid vesicles, are currently being evaluated as biomarkers. The consequences of their differential association lipids/vesicles for stability and use biomarkers largely unexplored subject present study. Methods levels a set selected microRNAs were determined quantitative reverse-transcription PCR after extraction from sera or vesicle- non-vesicle fractions prepared sera....
Background MicroRNA-21 (miR-21) is up-regulated in tumor tissue of patients with malignant diseases, including hepatocellular carcinoma (HCC). Elevated concentrations miR-21 have also been found sera or plasma from malignancies, rendering it an interesting candidate as serum/plasma marker for malignancies. Here we correlated serum levels clinical parameters different stages chronic hepatitis C virus infection (CHC) and CHC-associated HCC. Methodology/Principal Findings 62 CHC patients, 29...
Inherently complex, lignin-derived aromatic monomers comprising valuable structural moieties present in many pharmaceuticals would serve as ideal substrates for the construction of biologically active molecules. Here, we describe a strategy that incorporates all intrinsic functional groups platform chemicals obtained by lignin depolymerization into value-added amines, using sustainable catalytic methods and benign solvents. Our strikingly efficient protocol provides access to libraries...
In this study, we synthesized a library of eNTRy-rule-compliant compounds by introducing ionizable nitrogen atoms to an antimalarial compound. These positively charged derivatives gained activity against both Gram-negative and -positive bacteria, Mycobacterium tuberculosis, boosted Plasmodium falciparum inhibition the double-digit nanomolar range. Overcoming remaining inside cell envelope bacteria (GNB) is one major difficulties in antibacterial drug discovery development. The eNTRy rules (N...
Elevation of the intracellular cAMP concentration ([cAMP]i) regulates metabolism, cell proliferation, and differentiation plays roles in memory formation neoplastic growth. mediates its effects mainly through activation protein kinase A (PKA) as well Epac1 Epac2, exchange factors activating small GTPases Rap1 Rap2. However, how utilizes these effectors to induce distinct biological responses is unknown. We here studied specific PKA Epac neuroendocrine PC12 cells. In cells, elevation [cAMP]i...
Androgens are well-known to stimulate prostate cancer (PC) growth. Thus, blockade of androgen production in testes and adrenals by CYP17 inhibition is a promising strategy for the treatment PC. Moreover, many PC patients suffer from glucocorticoid overproduction, importantly mutated receptors can be stimulated glucocorticoids. In this study, first dual inhibitor CYP11B1 (the enzyme responsible last step biosynthesis) described. A series biphenylmethylene pyridines has been designed,...
Highly promising preclinical data obtained in cultured cells and nude mice bearing xenografts contrast with the rather modest clinical efficacy of Polo-like kinase 1 (Plk1) inhibitors. In present study, we investigated if Plk1 might be a suitable target hepatocellular carcinoma (HCC) genetically engineered mouse tumor model that well reflects cell micro-environmental features naturally occurring cancers to study anti-Plk1 therapy. Analysis expression human HCC samples confirmed express much...
The bacterial RNA polymerase (RNAP) is a validated target for broad spectrum antibiotics. However, the efficiency of drugs reduced by resistance. To discover novel RNAP inhibitors, pharmacophore based on alignment described inhibitors was used virtual screening. In an optimization process hit compounds, derivatives with improved in vitro potency were discovered. Investigations concerning molecular mechanism inhibition reveal that they prevent protein-protein interaction (PPI) between σ(70)...
Target-directed dynamic combinatorial chemistry (tdDCC) enables identification, as well optimization of ligands for un(der)explored targets such the anti-infective target 1-deoxy-d-xylulose-5-phosphate synthase (DXPS). We report use tdDCC to first identify and subsequently optimize binders/inhibitors DXPS. The initial hits were also optimized their antibacterial activity against E. coli M. tuberculosis during subsequent runs. Using tdDCC, we able generate acylhydrazone-based inhibitors...
Secreted virulence factors like bacterial collagenases are conceptually attractive targets for fighting microbial infections. However, previous attempts to develop potent compounds against these metalloproteases failed achieve selectivity human matrix metalloproteinases (MMPs). Using a surface plasmon resonance-based screening complemented with enzyme inhibition assays, we discovered an N-aryl mercaptoacetamide-based inhibitor scaffold that showed sub-micromolar affinities toward collagenase...
The increasing emergence of antibiotic resistance necessitates the development anti-infectives with novel modes action. Targeting bacterial virulence is considered a promising approach to develop antibiotics reduced selection pressure. extracellular collagenase elastase (LasB) plays pivotal role in infection process Pseudomonas aeruginosa and therefore represents an attractive antivirulence target. Mercaptoacetamide-based thiols have been reported inhibit LasB as well collagenases from...
In light of the global antimicrobial-resistance crisis, there is an urgent need for novel bacterial targets and antibiotics with modes action. It has been shown that Pseudomonas aeruginosa elastase (LasB) Clostridium histolyticum (Hathewaya histolytica) collagenase (ColH) play a significant role in infection process thereby represent promising antivirulence targets. Here, we report N-aryl-3-mercaptosuccinimide inhibitors target both LasB ColH, displaying potent activities vitro high...
Endoplasmic reticulum aminopeptidase 2 (ERAP2) is a key enzyme involved in the trimming of antigenic peptides presented by Major Histocompatibility Complex class I. It target growing interest for treatment autoimmune diseases and cancer immunotherapy. However, discovery potent selective ERAP2 inhibitors highly challenging. Herein, we have used kinetic target-guided synthesis (KTGS) to identify such inhibitors. Co-crystallization experiments revealed binding mode three different with...
Abstract Deriving active pharmaceutical agents from renewable resources is crucial to increasing the economic feasibility of modern biorefineries and promises alleviate critical supply‐chain dependencies in pharma manufacturing. Our multidisciplinary approach combines research lignin‐first biorefining, sustainable catalysis, alternative solvents with bioactivity screening, an vivo efficacy study, a structural‐similarity search. The resulting path novel anti‐infective, anti‐inflammatory,...
Abstract Designing novel candidates as potential antibacterial scaffolds has become crucial due to the lack of new antibiotics entering market and persistent rise in multidrug resistance. Here, we describe a class potent agents based on 5‐aryl‐ N 2 , 4 ‐dibutylpyrimidine‐2,4‐diamine scaffold. Structural optimization focused 5‐aryl moiety bioisosteric replacement side chain linker atom. Screening synthesized compounds panel bacterial strains, including gram‐positive Staphylococcus aureus...
Energy-coupling factor transporters (ECFTs) are membrane-bound ATP-binding cassette (ABC) in prokaryotes that found pathogens against which novel antibiotics urgently needed. To date, just 54 inhibitors of three molecular-structural classes with mostly weak inhibitory activity known. Target repurposing is a strategy transfers knowledge gained from well-studied protein family to under-studied targets phylogenetic relation. Forty-eight human ABC known may harbor structural motifs similar ECFTs...
Down-modulation of target molecules in tumor cells by small interfering (si) RNAs is a promising anti-cancer strategy. A major challenge this approach the loss silencing activity siRNAs vivo. Our study aimed at investigating influence serum compartment on anti-tumor siRNA directed against Polo-like kinase 1 (Plk1), mitosis-associated serine/threonine kinase. The data showed that siRNA-induced suppression Plk1 expression effectively reduced viable cell mass and increased apoptosis several...
CYP11B1 is the key enzyme in cortisol biosynthesis, and its inhibition with selective compounds a promising strategy for treatment of diseases associated elevated levels, such as Cushing's syndrome or metabolic disease. Expanding on previous study from our group resulting first potent rather inhibitor described so far (1, IC50 = 152 nM), we herein describe further optimizations imidazolylmethyl pyridine core. Five among 42 substances synthesized showed values below 50 nM. Most interesting...
A series of novel RNA polymerase (RNAP) inhibitors with antibacterial activity was designed and synthesized.