A supramolecular host for phosphatidylglycerol (PG) lipids with antibacterial activity

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 H-1 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 x 10(3) M-1, function as antibacterial agents against Gram-positive bacteria (MIC = 12.5-25 mu M), 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.

Automated summary

This study reports a set of neutral small molecules that selectively recognize bacterial lipids and exhibit antibacterial activity by binding to the headgroup of PG lipids, altering membrane fluidity, causing membrane depolarization, and ultimately leading to cell death.