Recognition of bacterial lipid headgroups by fluorescent crown ether-naphthalimides

Abstract

The increasing incidence of antibiotic- resistant bacterial strains is a significant threat to human health. New antimicrobial mechanisms that feature reduced resistance potential are necessary to slow down the rapid evolution of bacteria and to develop more selective treatment. Large crown ethers are known to actively hydrogen bond with ammonium groups (R-NH3+). Such ammonium group binding can be used to molecularly recognize the terminal ammonium unit present in the bacterial membrane lipid, “POPE.” This selective binding would be advantageous in such bacterial lipids present in mammalian hosts, which express lipid “POPC,” which lack the N-H capable of crown interaction. A fluorescently labeled crown ether was synthesized by palladium- catalyzed cross coupling of a 4-bromonapthalimide with 1-aza-18-crown-6. The crown-naphthalimide conjugate is strongly luminescent in nonpolar, organic solvents like dichloromethane and 1-octanol, but is quenched in polar solution such as aqueous phosphate buffer. The integrated fluorescence intensity of the conjugate is approximately three times greater in the presence of POPC liposomes than POPE liposomes, suggesting that the compound may be able to discriminate between mammalian and bacterial cell membranes. While fluorescence spectrophotometry concurs with the original proposal of observable POPE lipid selectivity, other data revealed otherwise. DFT optimization treatments were run to foretell possible interactions and orientations of the desired molecules. The computational analysis predicts that the ammonium group of POPE favors strong hydrogen binding within the crown, however proton NMR and ESI-MS studies have so far not confirmed that this binding mode is operative.