A supramolecular host for phosphatidylglycerol (PG) lipids with antibacterial activity. Issue 30 (22nd December 2021)

• Record Type: Journal Article
• Authors: Williams, Elliot S.; Gneid, Hassan; Marshall, Sarah R.; González, Mario J.; Mandelbaum, Jorgi A.; Busschaert, Nathalie
• Is Part Of: Organic & biomolecular chemistry. Volume 20:Issue 30(2022)
• Page Start: 5958
• Page End: 5966
• Publication Date: 2021-12-22
• Subjects: Chemistry, Organic -- Periodicals; Bioorganic chemistry -- Periodicals; Chemistry, Physical organic -- Periodicals; 547
• DOI: 10.1039/d1ob02298a
• Languages: English
• ISSNs: 1477-0520

Abstract

Abstract : Various small molecules containing boronic acid and urea functionalities are shown to bind selectively to the bacterial lipid PG (phosphatidylglycerol) and exert antibacterial activity through a membrane-related mechanism. 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 1 H 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 × 10 3 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.