Synthesis and efflux measurements of ammonium picket porphyrin molecules that target phosphatidylglycerol (PG), a lipid found in bacterial plasma membrane

Abstract

Phosphatidylglycerol (PG), is a major lipid component of bacterial plasma membranes and it is not widely found in eukaryotes, making PG a potentially selective target for antibacterial drugs. This report describes the synthesis of several ammonium-picket porphyrin molecules that are able to bind to the phosphatidylglycerol (PG) lipid head group. The binding pocket of the ammoniumpicket- porphyrin molecules was complementary for the PG head group and interacts with both the phosphate anion portion and neutral glycerol portion of the PG lipid head group. Structural characterizations and binding studies were determined using NMR experiments. Efflux measurements with synthetic vesicles were performed to demonstrate, ammonium-picketporphyrin receptors increase the membrane permeability upon binding to PG. Cell lysis experiments were performed to determine the ability of the ammonium-picket-porphyrin molecules to pass through outer membrane layers of both Gram-positive and Gram-negative bacterial cell walls and bind to the components of the cytoplasmic membrane. Molecular modeling and molecular dynamic simulations were performed to corroborate the binding motif and also to understand membrane permeability.