Vitamin E-poly(2-oxazolin)-ciprofloxacin conjugates that enter bacterial cells via their efflux pumps

Rendering established antibiotics by derivatization or formulation is a promising way to quickly obtain higher active antibiotics and to address antibiotic resistant bacterial strains. The antibiotic ciprofloxacin (CIP) conjugated with amphiphilic blockcopoly(2-oxazoline)s (POx) shows greatly enhanced antimicrobial activity, reduces resistance formation, and is active against CIP-resistant bacterial cells with overexpressed efflux pumps. In order to design CIP conjugates with comparable performance, but higher biocompatibility, the hydrophobic POx-block was substituted by a modified α-Tocopherol (VitE), which is predominantly referred to as vitamin E. Modification of VitE with 4-bromomethylbenzoyl bromide leads to a highly active initiator for POx synthesis. Using this initiator for the living cationic polymerization of 2-methyl-2-oxazoline leads to fully end-group functionalized PMOx. Conjugation of these polymers with CIP results in non-cytotoxic conjugates with improved CIP activity. These VitE-PMOx-EDA-xCIP conjugates enter E. coli cells via their efflux pumps. In case of E. coli with overexpressed efflux pumps (typical for resistant bacteria), the molar activity of the novel CIP conjugates is up to 100 times higher than free CIP, indicating potential of polymer conjugation with antibiotics to overcome bacterial resistances.[Formula: see text]