A5058170669- Antibiotic Resistance in Bacteria
- Antimicrobial Peptides and Activities
- Microbial Natural Products and Biosynthesis
- Carbohydrate Chemistry and Synthesis
- Glycosylation and Glycoproteins Research
- Enzyme Production and Characterization
- Cannabis and Cannabinoid Research
- Biochemical and Structural Characterization
- Antibiotics Pharmacokinetics and Efficacy
- Click Chemistry and Applications
- Enzyme Structure and Function
- Pneumocystis jirovecii pneumonia detection and treatment
- Cancer therapeutics and mechanisms
- X-ray Diffraction in Crystallography
- Biochemical and Molecular Research
- Nanocluster Synthesis and Applications
- Antimicrobial Resistance in Staphylococcus
- Marine Sponges and Natural Products
- Synthesis of β-Lactam Compounds
- Crystallization and Solubility Studies
- Metal complexes synthesis and properties
- Supramolecular Chemistry and Complexes
- Pancreatic function and diabetes
- Pneumonia and Respiratory Infections
- Sleep and Wakefulness Research
Leiden University
2019-2024
Oncode Institute
2020
Abstract Bacteria have evolved resistance to nearly all known antibacterials, emphasizing the need identify antibiotics that operate via novel mechanisms. Here we report a class of allosteric inhibitors DNA gyrase with antibacterial activity against fluoroquinolone-resistant clinical isolates Escherichia coli . Screening small-molecule library revealed an initial isoquinoline sulfonamide hit, which was optimized medicinal chemistry efforts afford more potent LEI-800. Target identification...
With increasing rates of resistance toward commonly used antibiotics, especially among Gram-negative bacteria, there is renewed interested in polymyxins. Polymyxins are lipopeptide antibiotics with potent anti-Gram-negative activity and generally believed to target lipid A, the lipopolysaccharide (LPS) anchor found outer membrane bacteria. To characterize stereochemical aspects their mechanism(s) action, we synthesized full enantiomers polymyxin B nonapeptide (PMBN). Both compounds were...
Antibiotic resistance is reaching alarming levels, demanding for the discovery and development of antibiotics with novel chemistry mechanisms action. The recently discovered antibiotic cacaoidin combines characteristic lanthionine residue lanthipeptides linaridin-specific N-terminal dimethylation in an unprecedented N-dimethyl ring, being therefore designated as first class V lanthipeptide (lanthidin). Further notable features include high D-amino acid content a unique disaccharide...
Gram-positive bacterial infections present a major clinical challenge, with methicillin- and vancomycin-resistant strains continuing to be cause for concern. In recent years, semisynthetic vancomycin derivatives have been developed overcome this problem as exemplified by the clinically used telavancin, which exhibits increased antibacterial potency but has also raised toxicity concerns. Thus, glycopeptide antibiotics enhanced activities improved safety profiles are still necessary. We...
Multidrug-resistant bacteria pose a serious global health threat as antibiotics are increasingly losing their clinical efficacy. A molecular level understanding of the mechanism action antimicrobials plays key role in developing new agents to combat antimicrobial resistance. Daptomycin, only clinically used calcium-dependent lipopeptide antibiotic, selectively disrupts Gram-positive bacterial membranes illicit its bactericidal effect. In this study, we use isothermal titration calorimetry...
Phenotypic screening is a powerful approach to identify novel antibiotics, but elucidation of the targets responsible for antimicrobial activity often challenging in case compounds with polypharmacological mode action. Here, we show that activity-based protein profiling maps target interaction landscape series 1,3,4-oxadiazole-3-ones identified phenotypic screen have high antibacterial potency against multidrug-resistant Staphylococcus aureus. In situ competitive and comparative chemical...
Abstract The prevalence of life‐threatening, drug‐resistant microbial infections has challenged researchers to consider alternatives currently available antibiotics. Teixobactin is a recently discovered “resistance‐proof” antimicrobial peptide that targets the bacterial cell wall precursor lipid II. In doing so, teixobactin exhibits potent activity against wide range Gram‐positive organisms. Herein we demonstrate and several structural analogues are capable binding II from both Gram‐negative...
The increasing prevalence of metallo-β-lactamase (MBL)-expressing bacteria presents a worrying trend in antibiotic resistance. MBLs rely on active site zinc ions for their hydrolytic activity and the pursuit MBL-inhibitors has therefore involved investigation chelators. To ensure that such chelators specifically target MBLs, series cephalosporin prodrugs two potent zinc-binders: dipicolinic acid (DPA) 8-thioquinoline (8-TQ) was prepared. Although both DPA 8-TQ bind free very tightly (Kd...
Two fluorescent, stable Pt 2 L 4 nanocages are developed. have alternated cytotoxicity and display diverse cell uptake in vivo making the versitale interesting candidates for further delivery toxicity studies.
Bacitracin is a macrocyclic peptide antibiotic that widely used as topical treatment for infections caused by gram-positive bacteria. Mechanistically, bacitracin targets bacteria specifically binding to the phospholipid undecaprenyl pyrophosphate (C 55 PP), which plays key role in bacterial lipid II cycle. Recent crystallographic studies have shown when bound C PP, adopts highly ordered amphipathic conformation. In doing so, all hydrophobic side chains align on one face of bacitracin–C PP...
N-Acylphosphatidylethanolamine phospholipase D (NAPE-PLD) is regarded as the main enzyme responsible for biosynthesis of N-acylethanolamines (NAEs), a family bioactive lipid mediators. Previously, we reported N-(cyclopropylmethyl)-6-((S)-3-hydroxypyrrolidin-1-yl)-2-((S)-3-phenylpiperidin-1-yl)pyrimidine-4-carboxamide (1, LEI-401) first potent and selective NAPE-PLD inhibitor that decreased NAEs in brains freely moving mice modulated emotional behavior [Mock Nat Chem. Biol., 2020, 16,...
For canonical asparagine glycosylation, the primary amino acid sequence that directs glycosylation at specific residues is well-established. Here we reveal a recently discovered bacterial enzyme EarP, transfers rhamnose to arginine residue in its acceptor protein EF-P, specifically recognizes β-hairpin loop. Notably, while vitro rhamnosyltransferase activity of EarP abolished when presented with linear substrate peptide sequences derived from readily glycosylates same cyclized mimic....
Abstract Antibiotics, particularly the β‐lactams, are a cornerstone of modern medicine. However, rise bacterial resistance to these agents, through actions β‐lactamases, poses significant threat our continued ability effectively treat infections. Metallo‐β‐lactamases (MBLs) particular concern due their hydrolyze wide range β‐lactam antibiotics including carbapenems. For this reason there is growing interest in development MBL inhibitors as well novel that can overcome MBL‐mediated...
ABSTRACT The amino sugar N- acetylglucosamine (GlcNAc) plays a central role in primary metabolism and is key signaling molecule for the onset of morphological chemical differentiation Streptomyces . global nutrient-sensory regulator DasR acts as gatekeeper development streptomycetes, its activity modulated by aminosugar phosphates. Here, we report discovery novel pathway that governs GlcNAc sensing. GlcNAc-6P converted into toxic metabolite via two new enzyme functions, namely dehydration N...
Protein N -glycosylation is ubiquitously present in all domains of life, and confers a plethora functions to the protein including increased solubility, protection from degradation, interaction with receptors, activation for function. For canonical asparagine glycosylation, recognition sequence that directs glycosylation at specific residues well-established. It generally holds primary amino acid most important substrate recognition. Here we reveal recently discovered bacterial enzyme called...
<p>Protein <i>N</i>-glycosylation is ubiquitously present in all domains of life, and confers a plethora functions to the protein including increased solubility, protection from degradation, interaction with receptors, activation for function. For canonical asparagine glycosylation, recognition sequence that directs glycosylation at specific residues well-established. It generally holds primary amino acid most important substrate recognition. Here we reveal recently...
Phenotypic screening is a powerful approach to identify novel antibiotics against methicillin-resistant Staphylococcus aureus (MRSA) infection, but elucidation of the targets responsible for antimicrobial activity often challenging in case compounds with polypharmacological mode-of-action. Here, we show that activity-based protein profiling maps target interaction landscape series 1,3,4-oxadiazole-3-ones, identified phenotypic screen have high antibacterial potency multidrug resistant S....