ABSTRACT
Lipids fulfill a variety of important physiological functions, such as energy storage, providing a hydrophobic barrier, and signal transduction. Despite this plethora of biological roles, lipids are rarely considered a potential target for medical applications. Here, we report a set of neutral small molecules that contain boronic acid and urea functionalities to selectively recognize the bacterial lipid phosphatidylglycerol (PG). The affinity and selectivity was determined using 1H NMR titrations and a liposome-based Alizarin Red S assay. Minimum inhibitory concentrations (MIC) were determined to assess antibacterial activity. The most potent compounds display an association constant with PG in liposomes of at least 5 × 103 M-1, function as antibacterial agents against Gram-positive bacteria (MIC = 12.5-25 µM), and show little hemolytic activity. Mode of action studies suggest that the boronic acids bind to the headgroup of the PG lipids, which leads to a change in membrane fluidity and ultimately causes membrane depolarization and cell death.
Subject(s)
Anti-Bacterial Agents , Phosphatidylglycerols , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Gram-Positive Bacteria , Liposomes/chemistry , Microbial Sensitivity TestsABSTRACT
In this manuscript, we show that small-molecule-based anion transporters can significantly increase the permeability of carboxylic acid containing drugs across lipid bilayers of model vesicles. Due to the drug-like characteristics of the transporters, this finding could not only have implications for drug delivery, but also hints towards potential drug-drug and drug-food interactions.
Subject(s)
Carboxylic Acids/metabolism , Lipid Bilayers/metabolism , Small Molecule Libraries/metabolism , Biological Transport , Carboxylic Acids/chemistry , Cell Membrane Permeability , Drug Delivery Systems , Ion Transport , Lipid Bilayers/chemistry , Molecular Structure , Small Molecule Libraries/chemistryABSTRACT
Herein, we introduce a new method to optimize the properties of optical sensors, coined the transporter-liposome-fluorophore (TLF) approach. It is shown that this approach can greatly improve the selectivity of the sensor, increase the dynamic range and maintain the sensitivity of the original fluorophore.
ABSTRACT
An arginine derivative with a fluorescent side-chain, Boc-Arg(Nap)-OH, was prepared by palladium(0)-catalyzed coupling of Boc-Arg-OH with a 4-bromonaphthalimide. The presence of the fluorophore lowers the pKa of the side-chain guanidinium group by several orders of magnitude, to 9.0 (±0.1), allowing the derivative to access an electrically neutral protonation state that is not generally available to arginine itself. Computational modeling (DFT) predicts that protonation takes place at the side-chain CâN atom that bears the fluorophore. Calculated electronic absorptions for the protonated (356 nm) and neutral species (440 nm) are in good agreement with experiment. When irradiated with light, excited-state proton transfer (ESPT) occurs from cationic side-chains to suitably basic solvents, resulting in fluorescence emission from the neutral species. Arg(Nap) can be incorporated into peptides with sterically accessible N-termini using specially adapted conditions of solid-phase peptide synthesis.
