A5089050095- Antimicrobial Peptides and Activities
- Chemical Synthesis and Analysis
- Dendrimers and Hyperbranched Polymers
- Antimicrobial agents and applications
- vaccines and immunoinformatics approaches
- Biochemical and Structural Characterization
- Bacteriophages and microbial interactions
- Click Chemistry and Applications
- RNA Interference and Gene Delivery
- Polydiacetylene-based materials and applications
- Glycosylation and Glycoproteins Research
- Carbohydrate Chemistry and Synthesis
- Microbial Natural Products and Biosynthesis
- Trypanosoma species research and implications
- Machine Learning in Bioinformatics
- Computational Drug Discovery Methods
- Ubiquitin and proteasome pathways
- Antibiotic Resistance in Bacteria
- Advanced Drug Delivery Systems
- Bioactive Compounds and Antitumor Agents
- RNA and protein synthesis mechanisms
- Protein Degradation and Inhibitors
University of Bern
2017-2024
University of Cambridge
2021
New antibiotics are urgently needed to address multidrug-resistant (MDR) bacteria. Herein we report that second-generation (G2) peptide dendrimers bearing a fatty acid chain at the dendrimer core efficiently kill Gram-negative bacteria including Pseudomonas aeruginosa and Acinetobacter baumannii, two of most problematic MDR worldwide. Our active TNS18 is also against Gram-positive methicillin-resistant Staphylococcus aureus. Based on circular dichroism molecular dynamics studies, hypothesize...
We recently discovered that peptide dendrimers such as G3KL ((KL)8(KKL)4(KKL)2KKL, K = branching l-lysine) exert strong activity against Gram-negative bacteria including Pseudomonas aeruginosa, Acinetobacter baumannii, and Escherichia coli. Herein, we report a detailed mechanistic study using fluorescence labeled analogs bearing fluorescein (G3KL-Fluo) or dansyl (G3KL-Dansyl), which show similar bioactivity profile G3KL. Imaging bacterial killing by super-resolution stimulated emission...
Herein we report the discovery of antimicrobial bridged bicyclic peptides (AMBPs) active against Pseudomonas aeruginosa, a highly problematic Gram negative bacterium in hospital environment. Two these AMBPs show strong biofilm inhibition and dispersal activity enhance polymyxin, currently last resort antibiotic which resistance is emerging. To discover our used concept chemical space, well known area small molecule drug discovery, to define number test compounds for synthesis experimental...
We used nearest-neighbor searches in chemical space to improve the activity of antimicrobial peptide dendrimer (AMPD) G3KL and identified T7, which has an expanded range against Gram-negative pathogenic bacteria including Klebsiellae pneumoniae, increased serum stability, promising vivo infection model a multidrug-resistant strain Acinetobacter baumannii. Imaging, spectroscopic studies, structural from molecular dynamics simulations suggest that T7 acts through membrane disruption. These...
We report herein a new chemical platform for coupling chitosan derivatives to antimicrobial peptide dendrimers (AMPDs) with different degrees of ramification and molecular weights via thiol-maleimide reactions. Previous studies showed that simple incorporation AMPDs polymeric hydrogels resulted in loss antibacterial activity augmented cytotoxicity mammalian cells. have shown enabled the two compounds act synergistically. was preserved when incorporating AMPD conjugates into various...
Solid-phase peptide synthesis (SPPS) is usually performed with optically pure building blocks to prepare peptides as single enantiomers. Herein we report that SPPS using racemic amino acids provides stereorandomized (sr) peptides, containing up billions of different stereoisomers, well-defined HPLC peaks, mass products high yield, which can be used investigate bioactivity. To exemplify our method, show stereorandomization abolishes the membrane-disruptive effect α-helical amphiphilic...
The biosynthesis of eukaryotic lipid-linked oligosaccharides (LLOs) that act as donor substrates in protein N-glycosylation starts on the cytoplasmic side endoplasmic reticulum and includes sequential addition five mannose units to dolichol-pyrophosphate-GlcNAc2. These reactions are catalyzed by Alg1, Alg2 Alg11 gene products yield Dol-PP-GlcNAc2Man5, an LLO intermediate is subsequently flipped lumen reticulum. While purification active Alg1 has previously been described, have mostly studied...
Abstract The burden of bacterial wound infections has considerably increased due to antibiotic resistance most the currently available antimicrobial drugs. Herein, for first time, a chemical coupling two cationic N ‐aryl (pyridyl and aminocinnamyl) chitosan derivatives peptide dendrimers (AMPDs) different generations (first, second, third) via thioether‐haloacetyl reaction is reported. new chitosan‐AMPD conjugates show high selectivity by killing Pseudomonas aeruginosa very low toxicity...
Exploring chemical space can deliver novel antimicrobials against multidrug resistant bacteria.
Herein, we report X-ray crystal structures of 11–13 residue antimicrobial peptides (AMPs) active against Pseudomonas aeruginosa as complexes fucosylated d-enantiomeric sequences with the P. lectin LecB. These represent first short AMPs. In 24 individual eight different peptides, found mostly α-helices assembled two-helix or four-helix bundles a hydrophobic core and cationic residues pointing outside. Two analogs formed an extended structure engaging in multiple contacts lectin. Molecular...
Among synthetic analogues of antimicrobial peptides (AMPs) under investigation to address resistance, peptoids (N-alkylated oligoglycines) have been reported act both by membrane disruption and on intracellular targets. Here we gradually introduced peptoid units into the membrane-disruptive undecapeptide KKLLKLLKLLL test a possible transition toward targeting. We found that selected hybrids containing up five retained parent AMP's α-helical folding, disruption, effects against Gram-negative...
The initial transfer of a complex glycan in protein N-glycosylation is catalyzed by oligosaccharyltransferase (OST), which generally multisubunit membrane the endoplasmic reticulum but single-subunit enzyme (ssOST) some protists. To investigate reaction mechanism ssOST, we recombinantly expressed, purified and characterized STT3A from Trypanosoma brucei (TbSTT3A). We analyzed vitro activity TbSTT3A synthesizing fluorescently labeled acceptor peptides as well lipid-linked oligosaccharide...
A new family of cyclic antimicrobial peptides is reported targeting multidrug resistant<italic>Pseudomonas aeruginosa</italic>by membrane disruption.
There is an urgent need to develop new antibiotics against multidrug-resistant bacteria. Many antimicrobial peptides (AMPs) are active such bacteria and often act by destabilizing membranes, a mechanism that can also be used permeabilize other antibiotics, resulting in synergistic effects. We recently showed G3KL, AMP with multibranched dendritic topology of the peptide chain, permeabilizes inner outer membranes Gram-negative including strains, leading efficient bacterial killing. Here, we...
A previously unknown pH-effect on the antimicrobial activity of peptide dendrimers and polymyxin B against <italic>Klebsiella pneumoniae</italic> MRSA is reported.
We recently showed that solid-phase peptide synthesis using racemic amino acids yields stereorandomized peptides comprising all possible diastereomers as homogeneous, single-mass products can be purified by HPLC and stereorandomization modulates activity, toxicity, stability of membrane-disruptive cyclic linear antimicrobial (AMPs) dendrimers. Here, we tested if might compatible with target binding the example proline-rich AMP oncocin, which inhibits bacterial ribosome. Stereorandomization...
Abstract We used nearest‐neighbor searches in chemical space to improve the activity of antimicrobial peptide dendrimer (AMPD) G3KL and identified T7 , which has an expanded range against Gram‐negative pathogenic bacteria including Klebsiellae pneumoniae increased serum stability, promising vivo infection model a multidrug‐resistant strain Acinetobacter baumannii . Imaging, spectroscopic studies, structural from molecular dynamics simulations suggest that acts through membrane disruption....
Sharing capital ideas: The 2017 Frontiers in Medicinal Chemistry (FiMC) conference, organized jointly by the German Chemical Society, Pharmaceutical and Swiss was held at Department of Biochemistry University Bern February 2017. Herein we summarize many conference highlights, look forward to next FiMC meeting, be Jena (Germany) March 2018.
<p>Solid-phase peptide synthesis (SPPS) is usually performed with optically pure building blocks to prepare peptides as single enantiomers. Herein we report that SPPS using racemic amino acids provides stereorandomized (<i>sr</i>) peptides, containing up billions of different stereoisomers,<a> </a>as well-defined HPLC peak, mass products high yield, which can be used investigate bioactivity. To exemplify our method, show stereorandomization abolishes the...
Solid-phase peptide synthesis (SPPS) is usually performed with optically pure building blocks to prepare peptides as single enantiomers. Herein we report that SPPS using racemic amino acids provides stereorandomized ( sr ) peptides, containing up billions of different stereoisomers, well-defined HPLC peak, mass products high yield, which can be used investigate bioactivity. To exemplify our method, show stereorandomization abolishes the membrane disruptive effect α-helical amphiphilic...
The presence of ionizable groups in antimicrobial peptides (AMPs) often induces a pH-dependent activity. Herein we report that removing eight low p K amino termini peptide dendrimer (AMPD) G3KL provides XC1 with broader pH-activity range. Furthermore, raising the pH to 8.0 reveals strong activities against Klebsiella pneumoniae and methicillin resistant Staphylococcus aureus (MRSA) which these AMPDs are inactive at 7.4. We observe similar effect polymyxin B on MRSA. Binding experiments...
In our efforts to develop peptide dendrimers as a new class of antimicrobial peptides (AMPs) against Gram-negative bacteria, we investigated their activity at acidic and basic pH, which correspond the conditions site bacterial infections on skin or biofilms chronic wounds respectively. Removing eight low p K amino termini reference dendrimer G3KL by substituting N -terminal lysine residues with aminohexanoic acid provided XC1 broader pH-activity range. Furthermore, raising pH 8.0 revealed...