A5036416271- Antimicrobial Peptides and Activities
- Microbial Natural Products and Biosynthesis
- Antibiotic Resistance in Bacteria
- Biochemical and Structural Characterization
- Chemical Synthesis and Analysis
- Cancer therapeutics and mechanisms
- Phenothiazines and Benzothiazines Synthesis and Activities
- RNA and protein synthesis mechanisms
- Click Chemistry and Applications
- Bacteriophages and microbial interactions
- Bacterial Genetics and Biotechnology
- Antibiotics Pharmacokinetics and Efficacy
- Alkaloids: synthesis and pharmacology
- Synthesis of Indole Derivatives
- Bioactive Compounds and Antitumor Agents
- Synthesis and biological activity
- Supramolecular Self-Assembly in Materials
- Radical Photochemical Reactions
- Essential Oils and Antimicrobial Activity
- Antimicrobial agents and applications
- Carbohydrate Chemistry and Synthesis
Technische Universität Berlin
2016-2025
The peptide antibiotic albicidin is a DNA topoisomerase inhibitor with low-nanomolar bactericidal activity towards fluoroquinolone-resistant Gram-negative pathogens. However, its mode of action poorly understood. We determined 2.6 Å resolution cryoelectron microscopy structure ternary complex between Escherichia coli gyrase, 217 bp double-stranded fragment and albicidin. Albicidin employs dual binding mechanism where one end the molecule obstructs crucial gyrase dimer interface, while other...
Antibiotic resistance is a continuously increasing concern for public healthcare. Understanding mechanisms and their emergence crucial the development of new antibiotics effective use. The peptide antibiotic albicidin such promising candidate that, as gyrase poison, shows bactericidal activity against wide range gram-positive gram-negative bacteria. Here, we report discovery gene amplification–based mechanism that imparts an up to 1000-fold increase in levels albicidin. RNA sequencing...
The peptide albicidin represents a highly promising lead structure which is first-in-class antibiotic with remarkable potency against gram-negative bacteria. Past efforts in the synthesis of analogs focused on increasing hydrophilicity, broadening antibacterial profile and overcoming resistance. Herein, we present synthetic derivatives variations N-terminal building block characterize their activity DNA gyrase inhibition. Furthermore, show that N-terminus greatly affects binding to...
Natural products represent an important source of potential novel antimicrobial drug leads. Low production by microorganisms in cell culture often delays the structural elucidation or even prevents a timely discovery. Starting from anti-Gram-negative antibacterial compound albicidin produced Xanthomonas albilineans, we describe bioactivity-guided approach combined with non-targeted tandem mass spectrometry and spectral (molecular) networking for discovery compounds. We report eight new...
To investigate the pharmacophore regions of antibiotic albicidin, derivatives with variations on central amino acid were synthesized. Charged as well uncharged residues chosen to explore influence charge, chirality, and steric bulk. The bioactivity newly synthesized was determined by a microdilution technique obtain minimum inhibitory concentrations (MIC) values. compounds also tested in cell-free system information about their ability inhibit primary target, DNA gyrase. It then shown that...
The peptide antibiotic albicidin, which is synthesized by the plant pathogenic bacterium, Xanthomonas albilineans, represents most prominent member of a new class antibacterial gyrase inhibitors. It shows remarkable activities against Gram-positive and Gram-negative microorganisms. Its unique structure potentially lead for development an drug. Here we report synthesis 14 albicidin derivatives with structural variations at N-terminus, primarily investigating effects variation cinnamoyl,...
Abstract Albicidin is a recently described natural product that strongly inhibits bacterial DNA gyrase. The pronounced activity, particularly against Gram‐negative bacteria, turns it into promising lead structure for an antibacterial drug. Hence, structure–activity relationship studies are key the in‐depth understanding of structural features/moieties affecting gyrase inhibition, activity and overcoming resistance. 27 newly synthesized albicidins give profound insights possibilities...
A systematic pyridine-scan of the albicidin molecule provides a new lead structure with improved antimicrobial properties.
Abstract Infections caused by Staphylococcal and Micrococcal species represent a major public health burden. Although treatments do exist, these tend to be associated with cytotoxic effects; furthermore, the emergence of antimicrobial resistance presents an immediate challenge. New classes active compounds are required address threats human health. Here we present de novo peptidomimetic strategy that produces self‐assembling cationic antimicrobials. To identify candidate compound...
Lanthipeptides are ribosomally-synthesized natural products from bacteria featuring stable thioether-crosslinks and various bioactivities. Herein, we report on a new clade of tricyclic class-IV lanthipeptides with curvocidin Thermomonospora curvata as its first representative. We obtained crystal structures the corresponding lanthipeptide synthetase CuvL that showed circular arrangement kinase, lyase cyclase domains, forming central reaction chamber for iterative substrate processing...
The natural product albicidin is a highly potent inhibitor of bacterial DNA gyrase. Its outstanding activity, particularly against Gram-negative pathogens, qualifies it as promising lead structure in the search for new antibacterial drugs. However, we show here, N-terminal cinnamoyl moiety susceptible to photochemical E/Z isomerization. Moreover, newly formed Z isomer exhibits significantly reduced which hampers development and biological evaluation derivatives thereof. Hence, synthesized 13...
Albicidin is a potent antibacterial oligoaromatic peptide that susceptible to the protease AlbD, resistance factor. This potentially restricts use of albicidin as drug. To overcome this obstacle, we synthesized and evaluated six analogues with isosteric replacement key amide link. Protease stability was established while maintaining activity, including three up eight times higher activity compared natural albicidin.
Abstract Lanthipeptides are ribosomally‐synthesized natural products from bacteria featuring stable thioether‐crosslinks and various bioactivities. Herein, we report on a new clade of tricyclic class‐IV lanthipeptides with curvocidin Thermomonospora curvata as its first representative. We obtained crystal structures the corresponding lanthipeptide synthetase CuvL that showed circular arrangement kinase, lyase cyclase domains, forming central reaction chamber for iterative substrate...
Abstract Antibiotic resistance is a continuously increasing concern for public health care. Understanding mechanisms and their emergence crucial the development of new antibiotics effective use. Here, we report discovery gene amplification-based mechanism that imparts an up to 1000-fold increase in levels against antibiotic albicidin. We show this protects Salmonella Typhimurium Escherichia coli by copy number GyrI-like transcription regulator STM3175 (YgiV) which binds X-ray crystallography...