Siderophore-Linked Ruthenium Catalysts for Targeted Allyl Ester Prodrug Activation within Bacterial Cells.
Siderophore-Linked Ruthenium Catalysts for Targeted Allyl Ester Prodrug Activation within Bacterial Cells.
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DOI：
10.1002/chem.202202536
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发表时间：
2023-02-07
影响因子：
4.3
通讯作者：
Duhme-Klair, Anne-Kathrin
中科院分区：
文献类型：
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作者：
Southwell, James W.;Herman, Reyme;Raines, Daniel J.;Clarke, Justin E.;Boeswald, Isabelle;Dreher, Thorsten;Gutenthaler, Sophie M.;Schubert, Nicole;Seefeldt, Jana;Metzler-Nolte, Nils;Thomas, Gavin H.;Wilson, Keith S.;Duhme-Klair, Anne-Kathrin
由于耐药性上升，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，被称为铁载体的螯合分子被细菌释放以获得铁，已经研究了与抗菌剂的结合，导致临床批准的药物头孢地罗可。近年来，使用小分子催化剂在细胞内激活前药已显示出希望，在这里，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。合成了基于莫西沙星的前药，并在厌氧生物相关条件下证明了其催化剂介导的活化。在不存在催化剂的情况下，观察到的抗菌活性降低相比，阿西沙星对大肠杆菌K12（BW 25113）。研究了一系列铁载体连接的钌催化剂的前药活化，所有这些催化剂均显示出与前药的组合抗菌作用，而代表性实施例对哺乳动物细胞系显示出很小的毒性。通过采用互补细菌生长测定，发现含有基于儿茶酚和azotochelin的铁载体单元的缀合物最有希望用于细胞内前药活化。 联合细菌：研究了铁载体连接的钌催化剂在细胞内激活抗菌前药物。开发了氟喹诺酮前药，并显示其在微需氧、生物学相关条件下与催化剂相容。将催化剂和前药共同添加到大肠杆菌中显示出组合效应，其中二羟基苯甲酸和偶氮螯铁蛋白连接的催化剂显示出最有希望用于细胞摄取并因此用于细胞内前药活化。
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. Ganging up on bacteria: Siderophore‐linked ruthenium catalysts were investigated for the activation of an antibacterial prodrug within cells. A fluoroquinolone prodrug was developed and shown to be compatible with the catalysts under micro‐aerobic, biologically relevant conditions. The co‐addition of the catalysts and prodrug to E. coli showed a combinative effect, with the dihydroxybenzoic acid‐ and azotochelin‐linked catalysts showing most promise for cellular uptake and thus intracellular prodrug activation.
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DOI：
10.3390/antibiotics10060701
发表时间：
2021-06-11
期刊：
Antibiotics (Basel, Switzerland)
影响因子：
--
作者：
Alegun O;Pandeya A;Cui J;Ojo I;Wei Y
通讯作者：
Wei Y
DOI：
10.1073/pnas.1718635115
发表时间：
2018-04-17
影响因子：
11.1
作者：
Friedman, Elliot S.;Bittinger, Kyle;Wu, Gary D.
通讯作者：
Wu, Gary D.
影响因子：
16.6
作者：
Okamoto Y;Kojima R;Schwizer F;Bartolami E;Heinisch T;Matile S;Fussenegger M;Ward TR
通讯作者：
Ward TR
影响因子：
14.9
作者：
Aldred KJ;McPherson SA;Turnbough CL Jr;Kerns RJ;Osheroff N
通讯作者：
Osheroff N
影响因子：
11.8
作者：
Page, Malcom G. P.
通讯作者：
Page, Malcom G. P.