Carbapenems and Lipid Bilayers: Localization, Partitioning, and Energetics

Carbapenems are broad-spectrum antibiotics used today to treat otherwise antibiotic resistant bacteria. As their target transpeptidase is located within the periplasm of the Gram-negative bacteria, they can participate in nonspecific interactions between the inner leaflet of the outer membrane and the outer leaflet of the inner membrane. We, therefore, studied the interaction of the four most clinically relevant carbapenems, namely, imipenem, doripenem, ertapenem, and meropenem, with model phospholipid bilayers made of 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) using molecular dynamics (MD) simulations and X-ray diffraction at low and high concentration of the drugs corresponding to 1 and 8 mol % (with respect to the number of membrane lipids). Membrane solubility was found to decrease from imipenem to doripenem, ertapenem, and finally meropenem. At low concentrations, membrane insertion was found to be a two step process, where the drugs first adsorb to the lipid head groups before inserting thro...