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 coordinationdirected 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.Supporting information and the ORCID identification number(s) for the author(s) of this article can be found under: https://doi.

Antibody Mimics as Bio-orthogonal Catalysts for Highly Selective Bacterial Recognition and Antimicrobial Therapy

“…CuAAC and its related reactions have been successfully applied for biological macromolecule labeling, − anticancer prodrug activation, bacterial metabolism labeling, and so on . Although polymer-based bio-orthogonal nanocatalysts , and some prodrug activation strategies − are used for antibacterial applications, design and synthesis of a bio-orthogonal catalyst with recognition of specific target bacteria is highly desirable and urgent for in situ synthesis of antibacterial drugs.…”

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.…”

Activation of the Ir–N(pyridine) Bond in Half-Sandwich Tethered Iridium(III) Complexes

“…70−73 Encouraged by the results of tether ring activation upon biomolecule-responsive nucleophilic attack, we aimed to demonstrate that the cleavable Ir−N(py) bond in our iridium(III) tether system can provide the molecule with switchability to act as an artificial catalyst by trapping a hydride ion under biological conditions using sodium formate or NADH as the hydride source. 20,67,74,75 Controlled activation over a switchable system such as the pyridine tethered structure presented in this work might be useful to protect them against deactivation until reaching the target site, maintaining their ability to bioorthogonally react with endogenous and exogenous substrates at the intracellular level.…”