Nanostructured assemblies using synergic antimicrobial agents and toxin-responsive properties for the treatment of bone and joint infections due to Staphylococcus aureus – ANTIDOTE

Staphylococcal bone and joint infections (BJIs) are a significant cause of morbidity and mortality, and the number of cases continues to increase in elderly but also in younger populations. They represent a major public health issue. These infections are difficult to treat, leading to chronic and recurrent forms, notably due to the persistence of bacteria in bone cells and biofilms. Nano-engineered drug delivery systems are currently recognized as a new opportunity to overcome limitations associated with antimicrobial chemotherapy by delivering antibiotics not only close to extracellular bacteria, but also to intracellular and intra-biofilm targets. ANTIDOTE proposes to treat such severe BJIs due to Staphylococcus aureus (S. aureus) using original core-shell nano-assemblies allowing the incorporation of antibiotics and targeting the sites of infection and biofilms using biomimetic and “stealth” surface-engineered assemblies. The core of ANTIDOTE nano-assemblies with controlled sizes will correspond to a polymer nanoparticle. Antibiotics of interest to treat BJIs will be incorporated in this nanoparticle by mild environmentally friendly procedures. The shell of ANTIDOTE nano-assemblies will be composed of lipids. The lipid formulation will involve PEG-lipid conjugates with the aim of developing “stealth” injectable assemblies, protected from opsonisation. After evidencing the non-cytoxicity of these ANTIDOTE nano-assemblies, the proof of concept of their efficacy will be tested in vitro on planktonic bacteria and on bacterial biofilms, as well as in an ex vivo model of infected cells. ANTIDOTE involves a multi-disciplinary consortium with complementary skills in chemistry, physicochemistry, toxicology and microbiology (IMP, ISMO, CEA-INAC, CIRI-INSERM). The original approach proposed in ANTIDOTE might be a very attractive way both to drastically increase the antibacterial activity against pathogens and to prevent the emergence of resistant organisms.