Targeted Antibacterial Strategy Based on Reactive Oxygen Species Generated from Dioxygen Reduction Using an Organoruthenium Complex

Abstract

Pathogenic microorganisms pose a serious threat to global public health due to their persistent adaptation and growing resistance to antibiotics. Alternative therapeutic strategies are required to address this growing threat. Bactericidal antibiotics that are routinely prescribed to treat infections rely on hydroxyl radical formation for their therapeutic efficacies. We developed a redox approach to target bacteria using organotransition metal complexes to mediate the reduction of cellular O 2 to H 2 O 2 , as a precursor for hydroxyl radicals via Fenton reaction. We prepared a library of 480 unique organoruthenium Schiff-base complexes using a coordination-driven three-component assembly strategy and identified the lead organoruthenium complex Ru1 capable of selectively invoking oxidative stress in Gram-positive bacteria, in particular methicillin-resistant Staphylococcus aureus , via transfer hydrogenation reaction and/or single electron transfer on O 2 . This strategy paves the way for a targeted antimicrobial approach leveraging on the redox chemistry of organotransition metal complexes to combat drug resistance.

Metal complexes for catalytic and photocatalytic reactions in living cells and organisms

“…10). 44 The initial strategy proposed by the authors lies on the exploitation of endogenous formate as a hydride Fig. 10 ROS generation by a ruthenium(II) complex inside bacterial cells: (A) hydride transfer mechanism in formate abundant Gram + strains and (B) SET mechanism in formate deficient strains.…”

Transition Metal Scaffolds Used To Bring New‐to‐Nature Reactions into Biological Systems

“…In particular, a number of groups have demonstrated that half-sandwich arene ruthenium complexes are some of the most suitable for in vivo usage. [30][31][32][33][34][35][36][37][38][39][40][41][42] In a pioneering example of this field, the Meggers group showed that Cp*Ru(COD)Cl (Cp* = η 5 -pentamethylcyclopentadienyl, COD = η 4 -1,5-cyclooctadiene) 1 could be used to facilitate allylcarbamate (alloc) cleavage within living mammalian cells. [30] Subsequent studies have shown that besides alloc deprotection, [31] Cp*Ru(COD)Cl can also be used effectively for azide-thioalkyne cycloaddition.…”

“…[40] In one notable example, the Ang group set out to prepare and test a diverse library of 768 unique ruthenium arene Schiff-base complexes 6. [41,42] To facilitate this, they used a 3-component assembly method to screen and identify the highest yielding catalysts for sulfonyl azide reduction. As a result, they found 6 catalysts with high efficiencies to carry forward and showed that intracellular reactivity in bacteria was possible.…”

“…A likely explanation for its popularity may be a combination of its robust reactivity, high chemoselectivity, and the overall stability of its metal complexes. In particular, a number of groups have demonstrated that half‐sandwich arene ruthenium complexes are some of the most suitable for in vivo usage [30–42] . In a pioneering example of this field, the Meggers group showed that Cp*Ru(COD)Cl (Cp*=η 5 ‐pentamethylcyclopentadienyl, COD=η 4 ‐1,5‐cyclooctadiene) 1 could be used to facilitate allylcarbamate (alloc) cleavage within living mammalian cells [30] .…”

“…These includes catalysts with ligands derived from hydroxyquinolinate 3 , [38] acetonitrile 4 , [39] and phenylazopyridine 5 [40] . In one notable example, the Ang group set out to prepare and test a diverse library of 768 unique ruthenium arene Schiff‐base complexes 6 [41,42] . To facilitate this, they used a 3‐component assembly method to screen and identify the highest yielding catalysts for sulfonyl azide reduction.…”