Drug-design based on light controlled NO release nitrosyl ruthenium complexes: Antibacterial and wound healing agents – NOBacLight

Synthesis and physico-chemical characterisation in coordination and supramolecular chemistry

Partner 1: The highlight is the significant investment in the synthesis of 10 RuNO complexes with their complete characterisation. The work will lead to several publications.

Partner 2: The absence of toxicity of the trans(Cl,Cl)-[Ru(FT)Cl2NO]+ complex was demonstrated. This is a very important point because toxicity is only expected under the effect of light.

Partners 1/3: The highlight of these 18 months concerns the encapsulation of the trans(Cl,Cl)-[Ru(FT)Cl2NO]Cl nitrosyl complex in a chitosan/pluronic hydrogel and the photoliberation of NO following irradiation of this encapsulated complex.

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The next tasks are dedicated respectively to understand antimicrobial properties of these selected compounds and to determine their pro-healing properties both in 2D monolayer cultures and in 3D human tissue-engineered skin substitutes.

The results make it possible to consider several articles.

Cutaneous wound infections are a global problem with millions of people presenting infected wounds with cost of treatment running into millions of euros per year. The increasing costs for health care, as well as the management difficulty, make wound treatment an important clinical, social and economic problem. Moreover, due to the increasing rate of antimicrobial-resistant infections, different strategies may be conducted in parallel such as the development of traditional and “non-traditional” anti-microbial agents (agents that are not small-molecule drugs and/or do not act by directly targeting bacterial components necessary for bacterial growth). In addition during skin infection, healing is slowed down. In recent years, studies using nitrogen oxide (NO) to combat multi-drug resistant bacteria has gained a lot of attention. Moreover, it was shown that NO may have a beneficial effect on wound healing process. In a previous work, we have shown that nitric oxide ruthenium complexes (Ru-NO) are efficient NO photo-donors and that the controlled NO release was responsible for antibacterial activity. In this context, the NOBacLight Project aims at developing light controlled nitric oxide ruthenium complexes (RuNO) as “non-traditional” antimicrobial agents with a wound healing activity.This project is innovative because it allows a control of NO release at the target site preserving healthy cells.
. For this purpose, we will synthesize a compound library of the different photo-activable Ru-NO complexes and screen their bactericidal activities against Gram-negative and Gram-positive microorganisms developing or not an acquired antibioresistance. . We hypothesize that Ru-NO complexes may also display an attractive activity as pro-healing agents. We will test the capability of the selected Ru-NO complexes to induce human cutaneous cells proliferation/migration/differentiation after an injury. Moreover, we have the ambition to develop appropriate formulations for the best Ru-NO candidates for future therapeutic applications.

The NOBacLight project is organized into five scientific tasks. It needs the complementarity (chemistry, bacteriology and biology) and close interactions of the three groups to be properly led.
Task 1 will computationally design, synthetize and characterize the NO photo-release properties of a library of Ru-NO complexes.
Task 2 is dedicated to the biological screening of these compounds in order to select the two ones presenting efficient antimicrobial properties together with low to inexistent cytotoxicity for human cutaneous cells.
Tasks 3 and 4 are dedicated respectively to understand antimicrobial properties of these selected compounds and to determine their pro-healing properties both in 2D monolayer cultures and in 3D human tissue-engineered skin substitutes.
Task 5 was added in the project in order to develop the formulation of Ru-NO complexes for topical application.

The NOBacLight project lies at the boundary between coordination chemistry and photophysics, microbiology, cellular biology, tissue engineering. It needs expertises in four different areas that are covered by the three partners. The project will have a high impact in the field of knowledge on “non-traditional” anti-bacteria agents and the design of new light controlled NO releasing compounds as antimicrobial drugs and wound healing agents. The final objective of this project is to fill the current gap between existing infections involving resistant bacteria and/or multispecies consortia and the strong need for targeted (local and rapidly efficient) alternative solutions in skin infections and wound control. This type of strategy will find a large variety of medical applications such as in surgery and in a larger extent for the treatment of severe cutaneous infections.