Lysenko Vladyslav, Gao Mei-Ling, Sterk Fabienne A C, Innocenti Paolo, Slingerland Cornelis J, Martin Nathaniel I
Biological Chemistry Group, Institute of Biology Leiden, Leiden University, Sylviusweg 72, 2333 BE Leiden, The Netherlands.
ACS Infect Dis. 2025 Aug 8;11(8):2301-2309. doi: 10.1021/acsinfecdis.5c00311. Epub 2025 Jul 5.
The growing concern over antibiotic resistance has sparked increased attention toward developing alternative antibiotic strategies. One promising approach, known as the "Trojan horse" strategy, involves the use of siderophores to hijack bacteria's iron transport systems as a way of delivering antibiotics inside the bacterial cell. This method is particularly promising in tackling Gram-negative bacteria, which have an outer membrane that many antibiotics cannot penetrate. One such antibiotic is rifampicin, a drug used to treat tuberculosis and infections caused by Gram-positive bacteria. Although rifampicin binds to a highly conserved bacterial RNA subunit, its activity is generally poor against Gram-negative bacteria due to their outer membrane. Aiming to expand rifampicin's efficacy, we here report the design and synthesis of several rifampicin-siderophore conjugates that exhibit enhanced activity against Gram-negative pathogens. Our findings indicate that the structural features of both the linker and catechol are crucial for the activity of conjugates with compound , wherein rifampicin is connected to chlorocatechol via a short ester linker, showing an up to 32-fold improvement in activity.
对抗生素耐药性的日益关注引发了人们对开发替代抗生素策略的更多关注。一种有前景的方法，即所谓的“特洛伊木马”策略，涉及利用铁载体劫持细菌的铁运输系统，以此将抗生素输送到细菌细胞内部。这种方法在对付革兰氏阴性菌方面特别有前景，因为革兰氏阴性菌有一层许多抗生素无法穿透的外膜。利福平就是这样一种抗生素，它是一种用于治疗结核病和革兰氏阳性菌引起的感染的药物。尽管利福平与一种高度保守的细菌RNA亚基结合，但其对革兰氏阴性菌的活性通常较差，原因在于它们的外膜。为了扩大利福平的疗效，我们在此报告了几种利福平-铁载体缀合物的设计与合成，这些缀合物对革兰氏阴性病原体表现出增强的活性。我们的研究结果表明，连接子和儿茶酚的结构特征对于与化合物缀合物的活性至关重要，其中利福平通过一个短酯连接子与氯儿茶酚相连，活性提高了多达32倍。
