Harnessing Endogenous Formate for Antibacterial Prodrug Activation by in cellulo Ruthenium‐Mediated Transfer Hydrogenation Reaction

Abstract

The abundance and evolving pathogenic behavior of bacterial microorganisms give rise to antibiotic tolerance and resistance which pose a danger to global public health. New therapeutic strategies are needed to keep pace with this growing threat. We propose a novel approach for targeting bacteria by harnessing formate, a cell metabolite found only in particular bacterial species, to activate an antibacterial prodrug and selectively inhibit their growth. This strategy is premised on transfer hydrogenation reaction on a biorthogonal substrate utilizing native formate as the hydride source as a means of uncaging an antibacterial prodrug. Using coordination‐directed 3‐component assembly to prepare a library of 768 unique Ru–Arene Schiff‐base complexes, we identified several candidates that efficiently reduced sulfonyl azide functional group in the presence of formate. This strategy paves the way for a new approach of targeted antibacterial therapy by exploiting unique bacterial metabolites.

Metals to combat antimicrobial resistance

“…One example is catalytic metallodrugs, which are a relatively new concept and are generally studied for cancer treatment 275 , 276 . Recent studies by Ang and co-workers 277 showcased the potential of catalytic metal complexes as antimicrobial agents. They developed tailored ruthenium complexes to specifically activate an azide-bearing antibiotic prodrug inside bacteria in a catalytic reaction that involves endogenous formate.…”

Targeting Pathogenic Formate-Dependent Bacteria with a Bioinspired Metallo–Nitroreductase Complex

“…The strategy utilizes organotransition metal fragments to stabilize labile Schiff-base ligands in aqueous media, thereby providing a driving force for the in situ assembly of the complexes. − We further established a reliable fluorogenic reaction-based screening platform to uncover potential bioorthogonal substrate/catalyst pairs. Thus far, we have uncovered Ru–arene Schiff-base (RAS) complexes capable of using endogenous formate to reduce sulfonylazide prodrug to sulfanilamide, as well as molecular oxygen into hydrogen peroxide. , In both reaction schemes, the substrate underwent a one-step two-electron transfer mechanism through a Ru–hydride intermediate. We surmised that RAS complexes can be optimized as artificial NTRs to mediate the multistep six-electron nitroreduction reaction using formate as the cofactor because the most energetically demanding step in the envisaged reaction scheme would be the initial Ru–H formation (Schemes and b).…”

Injectable self-healing hydrogel fabricated from antibacterial carbon dots and ɛ-polylysine for promoting bacteria-infected wound healing

“…Multitudinous nanoscale germicides, such as noble metal (eg. Au, Ag, Pd, Ru, Pt) [4][5][6][7][8][9][10][11][12] nanoparticles (NPs), metallic oxide [13][14][15][16][17] (eg. ZnO, TiO 2 and CuO) NPs, and carbonaceous nanomaterials [18][19][20] have been exploited as antimicrobial alternatives, which exhibit high potency with broad spectrum antibacterial activity.…”