A5057718680- Bacterial biofilms and quorum sensing
- Antimicrobial Peptides and Activities
- Antibiotic Resistance in Bacteria
- Biochemical and Structural Characterization
- Botulinum Toxin and Related Neurological Disorders
- Research on Leishmaniasis Studies
- Pneumocystis jirovecii pneumonia detection and treatment
- Trypanosoma species research and implications
- Malaria Research and Control
- Phenothiazines and Benzothiazines Synthesis and Activities
- Antibiotics Pharmacokinetics and Efficacy
- Antimicrobial agents and applications
- Parkinson's Disease Mechanisms and Treatments
- Parasites and Host Interactions
- Signaling Pathways in Disease
- Drug-Induced Hepatotoxicity and Protection
- Pneumonia and Respiratory Infections
- Oral and gingival health research
- Bacteriophages and microbial interactions
- Neurological disorders and treatments
- Hereditary Neurological Disorders
- Synthesis and biological activity
- Drug Transport and Resistance Mechanisms
- Protein Interaction Studies and Fluorescence Analysis
- Computational Drug Discovery Methods
Helmholtz Centre for Infection Research
2020-2024
Helmholtz Institute for Pharmaceutical Research Saarland
2020-2024
University of Belgrade
2015-2019
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...
Antivirulence therapy has become a widely applicable method for fighting infections caused by multidrug-resistant bacteria. Among the many virulence factors produced Gram-negative bacterium Pseudomonas aeruginosa, elastase (LasB) stands out as an important target it plays pivotal role in invasion of host tissue and evasion immune response. In this work, we explored recently reported LasB inhibitor class α-benzyl-N-aryl mercaptoacetamides exploiting crystal structure one compounds. Our...
Infections caused by the Gram-negative pathogen Pseudomonas aeruginosa are emerging worldwide as a major threat to human health. Conventional antibiotic monotherapy suffers from rapid resistance development, underlining urgent need for novel treatment concepts. Here, we report on nontraditional approach combat P. aeruginosa-derived infections targeting its main virulence factor, elastase LasB. We discovered new chemical class of phosphonates with an outstanding in vitro ADMET and PK profile,...
The syntheses and antiplasmodial activities of various substituted aminoquinolines coupled to an adamantane carrier are described. compounds exhibited pronounced in vitro vivo activity against Plasmodium berghei the Thompson test. Tethering a fluorine atom aminoquinoline C(3) position afforded fluoroaminoquinolines that act as intrahepatocytic parasite inhibitors, with compound 25 having IC50 = 0.31 μM reducing liver load mice by up 92% at 80 mg/kg dose. Screening our peroxides inhibitors...
Extracellular virulence factors have emerged as attractive targets in the current antimicrobial resistance crisis. The Gram-negative pathogen Pseudomonas aeruginosa secretes factor elastase B (LasB), which plays an important role infection process. Here, we report a sub-micromolar, non-peptidic, fragment-like inhibitor of LasB discovered by careful visual inspection structural data. Inspired natural substrate, original fragment was successfully merged and grown. optimized is accessible via...
Drug-resistant pathogens pose a global challenge to public health as they cause diseases that are extremely difficult cure. Metallo-β-lactamases (MBLs) diverse set of zinc-containing enzymes catalyze the hydrolysis β-lactam drugs, including carbapenems, which considered last resort fight severe infections. To restore activity current antibiotics and offer an orthogonal strategy discovery new antibiotics, we have identified series polar N-aryl mercaptopropionamide derivatives potent...
Significantly more potent second generation 4-amino-7-chloroquinoline (4,7-ACQ) based inhibitors of the botulinum neurotoxin serotype A (BoNT/A) light chain were synthesized. Introducing an amino group at C(3) position cholate component markedly increased potency (IC50 values for such derivatives ranged from 0.81 to 2.27 μM). Two additional subclasses prepared: bis(steroidal)-4,7-ACQ and bis(4,7-ACQ)cholate derivatives; both classes provided with nanomolar-range potencies (e.g., Ki compound...
Malaria is a severe and life-threatening disease caused by Plasmodium parasites that are spread to humans through bites of infected Anopheles mosquitoes. Here, we report on the efficacy aminoquinolines coupled benzothiophene thiophene rings in inhibiting falciparum parasite growth. Synthesized compounds were evaluated for their antimalarial activity toxicity, vitro mice. Benzothiophenes presented this paper showed improved activities against chloroquine susceptible (CQS) strain, with...
In this Letter, a detailed analysis of 30 4-aminoquinoline-based compounds with regard to their potential as antileishmanial drugs has been carried out. Ten demonstrated IC50 < 1 μM against promastigote stages L. infantum and tropica, five showed intramacrophage amastigotes. Two dose-dependent enhancement NO ROS production by bone marrow-derived macrophages remarkable reduction parasite load in vivo, advantage being short-term orally active. To the best our knowledge, is first example...
The synthesis and inhibitory potencies against botulinum neurotoxin serotype A light chain (BoNT/A LC) using in vitro HPLC based enzymatic assay for various steroidal, benzothiophene, thiophene, adamantane 4-aminoquinoline derivatives are described. In addition, the compounds were evaluated activity BoNT/A holotoxin mouse embryonic stem cell derived motor neurons. Steroidal derivative 16 showed remarkable protection (up to 89% of uncleaved SNAP-25) even when administered 30 min...
Infections caused by the Gram-negative pathogen Pseudomonas aeruginosa are emerging worldwide as a major threat to human health. Conventional antibiotic monotherapy suffers from rapid resistance development, underlining urgent need for novel treatment concepts. Here, we report on non-traditional approach combat P. aeruginosa-derived infections targeting its main virulence factor, elastase LasB. We discovered new chemical class of phosphonates with an outstanding in vitro ADMET and PK...
Antimicrobial resistance is currently one of the serious global public health threats. Unlike conventional antimicrobial drugs, antivirulence agents disarm rather than kill bacterial pathogens and therefore represent an alternative option to skirt problem resistance. Pseudomonas aeruginosa elastase (LasB) Clostridium histolyticum collagenase (ColH) are extracellular proteases which play a critical role in establishment progression respective infection. In this study, we report modulation...
Dual inhibitors of two key virulence factors Pseudomonas aeruginosa , the lectin LecA and protease LasB, open up an opportunity in current antimicrobial-resistance crisis.
Abstract Extrazelluläre Virulenzfaktoren haben sich als attraktive Ziele in der aktuellen Antibiotikaresistenzkrise erwiesen. Der Gram‐negative Erreger Pseudomonas aeruginosa sezerniert den Virulenzfaktor Elastase B (LasB), eine wichtige Rolle im Infektionsprozess spielt. Hier berichten wir über einen submikromolaren, nicht‐peptidischen, fragmentartigen Inhibitor von LasB, durch sorgfältige visuelle Analyse Strukturdaten entdeckt wurde. In Anlehnung an das natürliche LasB‐Substrat wurde...