Siderophore‐Linked Ruthenium Catalysts for Targeted Allyl Ester Prodrug Activation within Bacterial Cells

Abstract

Due to rising resistance, new antibacterial strategies are needed, including methods for targeted antibiotic release. As targeting vectors, chelating molecules called siderophores that are released by bacteria to acquire iron have been investigated for conjugation to antibacterials, leading to the clinically approved drug cefiderocol. The use of smallmolecule catalysts for prodrug activation within cells has shown promise in recent years, and here we investigate siderophore-linked ruthenium catalysts for the activation of antibacterial prodrugs within cells. Moxifloxacin-based prodrugs were synthesised, and their catalyst-mediated activation was demonstrated under anaerobic, biologically relevant conditions. In the absence of catalyst, decreased antibacterial activities were observed compared to moxifloxacin versus Escherichia coli K12 (BW25113). A series of siderophore-linked ruthenium catalysts were investigated for prodrug activation, all of which displayed a combinative antibacterial effect with the prodrug, whereas a representative example displayed little toxicity against mammalian cell lines. By employing complementary bacterial growth assays, conjugates containing siderophore units based on catechol and azotochelin were found to be most promising for intracellular prodrug activation.

Ligand Modifications on a Cp(quinolate)Ru Catalyst to Improve Its Stability in a Bio-orthogonal Deprotection Reaction

“…Furthermore, the interruption of the PD-1/PD-L1 interaction of cancer cells with T cells by the nanobodies could reverse the exhaustion of T cells and restore antitumor immunity . Together with our group, Duhme-Klair and co-workers have shown that prodrug activation inside bacteria using similar Kitamura-type siderophore-linked Ru catalysts is also possible . In the process, it was discovered that the catalysts performed better under anaerobic conditions due to the oxygen sensitivity of the catalytically active intermediate.…”

Siderophore conjugates to combat antibiotic-resistant bacteria

“…[21][22][23] Others have already begun to explore the potential for other metal-based SAC approaches such as the use of a siderophore-linked ruthenium catalyst for targeted intracellular prodrug activation. 126…”

Design and Synthesis of Novel Antimicrobial Agents

“…The two compounds demonstrated a strong affinity for Fe(III) and were used to internalize gallium as a hazardous metal. A Siderophore-linked ruthenium catalyst ( 155 , Figure 15 ) for the activation of an antibacterial prodrug inside cells was created and examined by Southwell et al [ 236 ]. Due to its tiny size and hydrophilic nature, the fluoroquinolone antibiotic moxifloxacin ( 156 , Figure 15 ) is mostly absorbed by bacteria through porins.…”