University of York, Department of Chemistry, Heslington, York, YO10 5DD, UK.
University of York, Department of Biology, Heslington, Wentworth Way, YO10 5DD, UK.
Chemistry. 2023 Feb 7;29(8):e202202536. doi: 10.1002/chem.202202536. Epub 2022 Dec 21.
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 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, 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.
由于耐药性不断上升，需要新的抗菌策略，包括靶向抗生素释放的方法。作为靶向载体，已经研究了细菌释放的螯合分子即铁载体与抗生素偶联，从而得到临床批准的药物头孢地尔。近年来，小分子催化剂用于细胞内前药激活的方法显示出很大的潜力，在此我们研究了铁载体连接的钌催化剂在细胞内激活抗菌前药的作用。合成了基于莫西沙星的前药，并在厌氧、生物学相关条件下证明了其在催化剂介导下的激活。在没有催化剂的情况下，与莫西沙星相比，前药对大肠杆菌 K12（BW25113）的抗菌活性降低。研究了一系列铁载体连接的钌催化剂对前药的激活作用，所有催化剂都显示出与前药的组合抗菌作用，而代表性的例子对哺乳动物细胞系的毒性较小。通过采用互补的细菌生长测定法，发现基于儿茶酚和氮杂环丁烷的铁载体单元的缀合物最有希望用于细胞内前药激活。
