Engineering Cationic Metallopolymers to Potentiate Antibiotics via Multiple Mechanisms - Abstract Polymeric biomaterials play a significant role in modern biomedical sciences, including the application of being used as antimicrobial agents. Bacterial infections have evolved into one of the most urgent global health threats, leading to increased healthcare cost, destruction of local tissues, patient disability, morbidity, and even death. Antibiotics, one of the most important developments in modern medicine, have saved millions of lives and continue to serve as the major therapy to treat bacterial infections. However, commonly-used antibiotics have diminished antimicrobial efficacies and/or are ineffective against numerous multidrug-resistant (MDR) bacterial pathogens. If more-effective strategies are not taken to prevent and treat bacterial infections, it has been predicted that by 2050 infections could claim 10 million lives with costs approaching $100 trillion (USD) dollars worldwide. Facing the mounting crisis on the rise of antibiotic-resistant bacteria, it is essential for innovating the continued use of existing antibiotics and for establishing a more sustainable portfolio of new antimicrobial therapies. We propose to develop platform biointerfaces technologies on a new class of cationic metallo- polymers. Macromolecular engineering enables controlled polymerization and chemoselective reactions, which allow the synthesis of polymers with precise compositions. These cationic metallo-polymers can substantially enhance the efficacy of antibiotics when they are combined. The antibiotics for antimicrobial screening include β-lactams, carbapenems, tetracyclines, aminoglycosides, etc. We are particularly addressing persister cells in the MDR forms of Gram- negative pathogens, such as those designated as “urgent threats” and “serious threats” by CDC. Our approaches aim to design biodegradable polymer compositions that can install cationic cobaltocenium at the side chain, which can target cell membranes and outer leaflets. There are four objectives involved in this project: (1) to screen biodegradable polymer compositions for combinations with antibiotics against stationary phase bacteria or persisters; (2) to uncover synergistic mechanisms of action in polymer-antibiotic combinations; (3) to evaluate biofilm eradication and inhibition of lead combinations; (4) to evaluate cytotoxicity and conduct in vivo efficacy of infections. Our research and discoveries could provide a new polymeric biomaterial platform to reinvigorate common antibiotics to kill MDR bacteria.
