新型铁载体-甲氨蝶呤抗菌缀合物的设计、合成及活性评价
Design, Synthesis and Antibacterial Activity Evaluation of Novel Siderophore-Methotrexate Conjugate
摘要
细菌多重耐药性（MDR）的日益蔓延对全球公共卫生构成重大威胁，然而现有抗生素的疗效正逐渐衰退，难以有效遏制这一严峻局面。针对此，药物再定位（drug repurposing）与结构修饰成为开发新型抗菌策略的有效途径。铁载体偶联策略（"特洛伊木马"）通过利用细菌铁摄取系统实现药物靶向富集，可显著降低宿主毒性并克服细菌外膜屏障。本团队前期研究表明，甲氨蝶呤（MTX）-铁载体缀合物可有效克服母药渗透性差及细胞毒性高的问题，对肺炎链球菌ATCC 49619的抗菌活性（MIC为1.72 nM）较母药提高逾1279倍，人细胞毒性降低逾2313倍。在此基础上，本研究设计并合成新型连接臂修饰的MTX-铁载体缀合物，旨在进一步优化药物稳定性、靶向释放效率及成药性。结果显示，新化合物对肺炎链球菌ATCC 49619的最小抑菌浓度（MIC）达0.49 nM，活性较前期化合物提高逾三倍，为拓展抗癌药物在抗菌领域的应用提供了新的实验依据。
Abstract
The escalating prevalence of bacterial multidrug resistance (MDR) poses a significant threat to global public health; however, the efficacy of available antibiotics is progressively declining, rendering them inad equivuate to effectively combat this critical situation. In response, drug repurposing and structural modification have emerged as effective strategies for developing novel antibacterial therapies. The siderophore conjugation strategy ("Trojan horse" approach) achieves targeted drug enrichment via bacterial iron uptake systems, significantly reducing host toxicity while overcoming the bacterial outer membrane barrier. Our previous studies demonstrated that methotrexate (MTX)-siderophore conjugates effectively overcame the limitations of the parent drug, including poor permeability and high cytotoxicity, exhibiting over 1279-fold enhanced antibacterial activity against Streptococcus pneumoniae ATCC 49619 (MIC = 0.98 nM) and over 2313-fold reduced human cytotoxicity. Building upon these findings, this study designed and synthesized novel MTX-siderophore conjugates with modified linkers, aiming to further optimize drug stability, targeted release efficiency, and drug-likeness. The results revealed that the new compound achieved a MIC of 0.49 nM against S. pneumoniae ATCC 49619, representing over threefold improvement in potency compared to our previous lead compound, providing novel experimental evidence for expanding the application of anticancer agents in antimicrobial therapy.关键词
药物化学/铁载体/甲氨蝶呤/铁霉素/药物再定位Key words
pharmaceutical chemistry/ siderophore/methotrexate/sideromycin/drug repurposing引用本文复制引用
杜远江,郭键.新型铁载体-甲氨蝶呤抗菌缀合物的设计、合成及活性评价[EB/OL].(2026-03-27)[2026-03-28].http://www.paper.edu.cn/releasepaper/content/202603-265.学科分类
药学
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