Evaluation de l’activité antimicrobienne des complexes de ruthénium nitrosyle par photolibération de NO•

Increasing threat of antimicrobial resistance (AMR) and cutaneous wound infections are critical challenges for public health worldwide. Novel approaches beyond conventional antimicrobial agents are under development. Nitric oxide (NO•) is among rising agents with therapeutic effects in both wound healing and antimicrobial applications. Ruthenium nitrosyl (RuNO) complexes are promising exogenous NO• donors, and therefore antimicrobial agents for the treatment of cutaneous wound infections. A series of ten RuNO complexes with varying ligands, such as substituted terpyridine, acetylacetonate (acac), 17α-ethinylestradiol, and varying counterions (Cl- and PF6-), is synthesised and characterised. Their photo-induced NO• release properties were studied to ensure an efficient and controlled release of NO•, which are critical criteria of an ideal exogenous NO• donor. Other physico-chemical properties, such as solubility in water and hydrophilicity, were investigated at the same time. Upon irradiation, RuNO complexes exhibit significant microbicidal activities, against a broad spectrum of Gram-positive, Gram-negative bacteria, and fungi strains, such as Staphylococcus aureus CIP 4.83, Streptococcus pyogenes CIP 56.41T and Candida albicans IP 4872. Importantly, the complexes exhibit low activity in the dark, showcasing their potential for targeted NO• delivery only upon irradiation. The most promising candidate, trans(NO,OH)-[RuII(Fluorenyl-Terpy)NO(OH)Cl]Cl (FT-OH Cl complex), displays excellent microbicidal activity upon irradiation and a lack of cytotoxicity and phototoxicity towards primary human dermal fibroblasts, highlighting its potential for therapeutic applications in cutaneous wound management. Against aggregated communities of microorganisms, the form in which microorganisms are generally present on wounds, trans(NO,OH)-[RuII(Fluorenyl-Terpy)NO(OH)Cl]Cl showed promising antibiofilm activity. Staphylococcus aureus CIP 4.83 biofilm was significantly reduced upon photoactivation of the RuNO complex, allowing further investigation over the mechanism of action of NO•'s antimicrobial and antibiofilm activities. Overall, a comprehensive analysis of the antimicrobial and antibiofilm properties of RuNO complexes is provided by this thesis project. Their potential as NO• donors, and as a new generation of antimicrobials is highlighting, and demonstrates innovative approach for combating antimicrobial resistance and addressing the pressing need for effective treatments against wound infections.