Structure, toxicity and antibiotic activity of gramicidin S and derivatives

Development of new antibiotics is declining whereas antibiotic resistance is rising, heralding a post-antibiotic era. Antimicrobial peptides such as gramicidin S (GS), exclusively topically used due to its hemolytic side-effect, could still be interesting as therapeutic compounds. By modifying the amino-acid composition of GS, we synthesized GS analogues. We now show that derivative VK7 has a lower MIC (7.8–31.2 μg/ml, median 15.6 μg/ml) against strains of multi-drug resistant (MDR) Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa than GS has (3.9–62.5 μg/ml, median 31.3 μg/ml). Low MICs for both VK7 and GS were observed for Staphylococcus aureus and Enterococcus faecium

Paramagnetic chemical probes for studying biological macromolecules

Paramagnetic chemical probes have been used in electron paramagnetic resonance (EPR) and nuclear magnetic resonance (NMR) spectroscopy for more than four decades. Recent years witnessed a great increase in the variety of probes for the study of biological macromolecules (proteins, nucleic acids, and oligosaccharides). This Review aims to provide a comprehensive overview of the existing paramagnetic chemical probes, including chemical synthetic approaches, functional properties, and selected applications. Recent developments have seen, in particular, a rapid expansion of the range of lanthanoid probes with anisotropic magnetic susceptibilities for the generation of structural restraints based on residual dipolar couplings and pseudocontact shifts in solution and solid state NMR spectroscopy, mostly for protein studies. Also many new isotropic paramagnetic probes, suitable for NMR measurements of paramagnetic relaxation enhancements, as well as EPR spectroscopic studies (in particular double resonance techniques) have been developed and employed to investigate biological macromolecules. Notwithstanding the large number of reported probes, only few have found broad application and further development of probes for dedicated applications is foreseen.Macromolecular Biochemistr

Protein docking using an ensemble of spin labels optimized by intra-molecular paramagnetic relaxation enhancement

Macromolecular Biochemistr

Rigidified and Hydrophilic DOTA-like Lanthanoid Ligands: Design, Synthesis, and Dynamic Properties

Limiting the dynamics of paramagnetic tags is crucial for the accuracy of the structural information derived from paramagnetic nuclear magnetic resonance (NMR) experiments. A hydrophilic rigid 2,2 ',2 '', 2"'-( 1, 4,7, 10-tetraaz acyclo do de cane-1,4,7,10-tetrayl)tetraacetic acid (DOTA)-like lanthanoid complex was designed and synthesized following a strategy that allows the incorporation of two sets of two adjacent substituents. This resulted in a C2 symmetric hydrophilic and rigid macrocyclic ring, featuring four chiral hydroxyl-methylene substituents. NMR spectroscopy was used to investigate the conformational dynamics of the novel macrocycle upon complexation with europium and compared to DOTA and its derivatives. The twisted square antiprismatic and square antiprismatic conformers coexist, but the former is favored, which is different from DOTA. Two-dimensional 1H exchange spectroscopy shows that ring flipping of the cyclen-ring is suppressed due to the presence of the four chiral equatorial hydroxyl-methylene substituents at proximate positions. The reorientation of the pendant arms causes conformational exchange between two conformers. The reorientation of the coordination arms is slower when the ring flipping is suppressed. This indicates that these complexes are suitable scaffolds to develop rigid probes for paramagnetic NMR of proteins. Due to their hydrophilic nature, it is anticipated that they are less likely to cause protein precipitation than their more hydrophobic counterparts.Bio-organic SynthesisMacromolecular Biochemistr

Inhibiting and reversing amyloid-beta peptide (1-40) fibril formation with gramicidin S and engineered analogues

Biophysical Structural Chemistr