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Abstract:

Biofilm associated infections represent one of the most serious challenges of modern medicine. Ubiquitous and tenacious, biofilms have undermined the current antibiotic strategies fostering resistance development by increasing bacterial tolerance. The extracellular matrix, host of these bacterial sessile communities, plays a major role in the resilience of biofilms against common cleaning and disinfection procedures as well as antibiotic treatments. Extracellular polymeric substances (EPS) as polysaccharides and proteins are the main constituents of the biofilm matrix and the inhibition of their production has been our strategic goal in the past decade. The individuation of a new class of antibiofilm compounds based on 2-aminoimidazoles (2-AIs) signed the beginning of a new research line in our laboratories. 2-AIs exert their antibiofilm-specific activity through the inhibition of the production of EPS (i.e. cellulose and curli). Consequently, the structure of the biofilm is weakened, and bacterial cells become more susceptible to mechanical and chemical stresses. Our most advanced application strategy regards the preparation of coatings for indwelling devices such as orthopedic implants and vascular grafts. The treatment of infections associated with the contamination of these devices is complicated by the impossibility of directly reaching the infection site. In this work, we describe our latest findings in regard to the development of such antibiofilm coatings. In vitro activity studies and in vivo validation of an improved covalent coating for orthopedic implants are presented. Higher loading of the active compound was associated with higher in vitro activity and good in vivo biocompatibility. Furthermore, preventive in vivo activity studies suggested the effectiveness of the coating, especially in combination with antibiotic prophylaxis. Later, a comprehensive strategy has been designed to extend the impact of our antibiofilm coating in terms of materials and mode of action. A material-independent coating was described and validated in vitro. Moreover, optimization of the reaction conditions allowed for the development of a high-throughput screening methodology for antibiofilm coatings which was unprecedented in literature. Finally, a smart release coating was designed and validated through the newly optimized screening procedure. The release of the active compound was triggered by biofilm formation and allowed for activity on a spatially far surface. Its implementation with a covalent antibiofilm coating is expected to guarantee activity on both the implant and the surrounding tissues.