A5027160935- Antibiotic Resistance in Bacteria
- Antimicrobial Peptides and Activities
- Antibiotics Pharmacokinetics and Efficacy
- Microbial Natural Products and Biosynthesis
- Biochemical and Structural Characterization
- Pneumocystis jirovecii pneumonia detection and treatment
- Phenothiazines and Benzothiazines Synthesis and Activities
- Antimicrobial agents and applications
- Protein Degradation and Inhibitors
- Peptidase Inhibition and Analysis
- Bacterial Genetics and Biotechnology
- Bacterial biofilms and quorum sensing
- Synthesis and Catalytic Reactions
- Ubiquitin and proteasome pathways
- Antibiotic Use and Resistance
Leiden University
2017-2023
Brevicidine and laterocidine are two recently discovered lipopeptide antibiotics with promising antibacterial activity. Possessing a macrocyclic core, multiple positive charges, lipidated N-terminus, these lipopeptides exhibit potent selective activity against Gram-negative pathogens, including polymyxin-resistant isolates. Given the low amounts of brevicidine accessible by fermentation producing microorganisms, synthetic routes to present an attractive alternative. We here report convenient...
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...
Pentamidine, an FDA-approved antiparasitic drug, was recently identified as outer membrane disrupting synergist that potentiates erythromycin, rifampicin, and novobiocin against Gram-negative bacteria. The same study also described a preliminary structure-activity relationship using commercially available pentamidine analogues. We here report the design, synthesis, evaluation of broader panel bis-amidines inspired by pentamidine. present both validates previously observed synergistic...
Polymyxins are a class of lipopeptide anti-infective agents with potent and specific activity against Gram-negative bacteria. While toxicity concerns associated polymyxin B E (colistin) have historically limited their clinical application, today they increasingly used as last-resort antibiotics given the rise multidrug-resistant pathogens. The adverse side effects polymyxins well known, particularly related to nephrotoxicity. Here, we describe synthesis evaluation novel series analogues,...
In the hunt for new antibiotics with activity against Gram-negative pathogens, outer membrane β-barrel assembly machine (BAM) complex has become an increasingly interesting target. The recently reported BAM inhibitor, MRL-494, was discovered via a screening campaign molecules that target membrane. Notably, MRL-494 to be unintended byproduct generated during synthesis of unrelated compound, and as such no compound disclosed. We here present convenient reliable route scales well. antibacterial...
The continued rise of antibiotic resistance threatens to undermine the utility world’s current arsenal. This problem is particularly troubling when it comes Gram-negative pathogens for which there are inherently fewer antibiotics available. To address this challenge, recent attention has been focused on finding compounds capable disrupting outer membrane as a means potentiating otherwise Gram-positive-specific antibiotics. In regard, agents binding lipopolysaccharide (LPS) present in...
Most known β2-selective proteasome inhibitors suffer from relatively poor cell permeability as the result of a net positive charge caused by basic moiety at P1. In this paper, we describe synthesis oligopeptide vinyl sulfones that contain different amino acids bearing groups with reduced basicity P1 and/or P3. For this, developed first enantioselective lysine(4-ene) and lysine(4-yne). These acids, well histidine diaminopropionic-acid-glycine, were incorporated P3 positions sulfones. All...
A novel series of polymyxin analogues bearing a disulfide linked lipid tail are reported. The most promising variant identified exhibits antibacterial activity equipotent to that B and is >10-fold less toxic towards kidney cells.
Brevicidine and laterocidine are two recently discovered lipopeptide antibiotics with promising antibacterial activity. Possessing a macrocyclic core, multiple positive charges, lipidated N-terminus, these lipopeptides exhibit potent selective activity against Gram-negative pathogens, including polymyxin-resistant isolates. Given the low amounts of brevicidine accessible by fermentation producing microorganisms, synthetic routes to present an attractive alternative. We here report convenient...