Novel antibacterial strategies to combat biomaterial-associated infection

The use of medical devices has grown significantly over the last decades, and has become a major part of modern medicine and our daily life. The risk of infection is a significant problem with any inserted or implanted foreign body material, and is the number one cause of failure of implanted biomaterials. These so-called biomaterial-associated infections (BAI) are mainly caused by Staphylococcus aureus and Staphylococcus epidermidis. This thesis describes the development and characterization of novel antimicrobial agents and delivery systems, and their effectiveness in the prevention of BAI and other difficult-to-treat biofilm infections. The first strategy is based on a direct contact-killing approach. We describe the design and synthesis of a thin layer hydrogel with covalently attached synthetic antimicrobial peptides (AMPs) stabilized against proteolytic degradation. Another strategy to prevent BAI is the controlled release of antimicrobial agents, like chlorhexidine or synthetic AMPs, from a surface coating. All synthetic AMPs developed within this thesis have great potential for clinical application. Release of OP-145 was able to prevent S. aureus osteomyelitis in rabbits. The newly developed synthetic peptides, i.e. SAAP-145, SAAP-148, SAAP-276 and TC19, proved to have broad spectrum activity including activity against highly dangerous multi-drug resistant pathogens, to prevent biofilm formation, and to have in vivo activity, either in preventing biomaterial-associated or wounded skin infections. The results of the studies described in this thesis provide more insight in the pathogenesis of BAI and present novel prevention options in the fight against difficult-to-treat biofilm infection caused by multidrug-resistant pathogens.