Siderophore-linked Ruthenium Catalysts for Targeted Allyl Ester Prodrug Activation within Bacterial Cells

Chemistry. 2022 Nov 10. doi: 10.1002/chem.202202536. Online ahead of print.ABSTRACTDue to rising resistance, new antibacterial strategies are needed, including methods for targeted antibiotic release. As targeting vectors, chelating molecules released by bacteria to acquire iron called siderophores have been investigated for conjugation to antibacterials, leading to the clinically-approved drug cefiderocol. The use of small-molecule 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, whilst 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.PMID:36355416 | DOI:10.1002/chem.202202536
Source: Chemistry - Category: Chemistry Authors: Source Type: research