Iron transport-mediated drug delivery using mixed-ligand siderophore-beta-lactam conjugates
Iron transport-mediated drug delivery using mixed-ligand siderophore-beta-lactam conjugates
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DOI：
10.1016/s1074-5521(96)90167-2
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发表时间：
1996-12-01
影响因子：
--
通讯作者：
Miller, MJ
中科院分区：
文献类型：
--
作者：
Ghosh, A;Ghosh, M;Miller, MJ
背景：铁的同化对微生物的生长至关重要。大多数微生物合成并排泄称为铁载体的低分子铁络合剂，通过活跃的运输过程隔离和输送铁。特定的外膜蛋白识别、结合和启动物种选择性铁铁载体复合体的运输。生物体通常对多种类型的铁载体有特定的受体，可能是为了确保充分获取对它们的生长至关重要的铁。药物与合成羟基甲酸酯或邻苯二酚铁载体组分的偶联可以促进活性铁转运介导的药物传递。虽然铁载体-药物结合物的耐药性经常通过选择缺乏相应的铁载体选择性外膜受体的突变株来发生，但突变株在缺铁条件下和体内存活的能力较差。我们预计，混合配体铁载体药物结合物的合成将通过多个铁受体识别和转运过程来主动给药，进一步降低耐药突变株存活的可能性。结果：混合配体铁载体药物结合物是通过将异羟甲酸酯和邻苯二酚组分结合在一个化合物中而合成的，该化合物可以螯合铁，并且还包含与氨头孢菌素的共价键，作为代表性药物。在野生型微生物和某些外膜铁转运受体缺乏的突变体中，新的结合物似乎被多种活跃的铁转运过程同化。结论：主动铁转运介导的药物输送的概念现在可以扩展到可以通过多个外膜受体进入细胞的药物结合物。对这种结合物具有抗性的突变体在铁的吸收方面应该受到严重的损害，因此特别容易发生铁饥饿。(C)现代生物有限公司。
Background: Assimilation of iron is essential for microbial growth. Most microbes synthesize and excrete low molecular weight iron chelators called siderophores to sequester and deliver iron by active transport processes. Specific outer membrane proteins recognize, bind and initiate transport of species-selective ferric siderophore complexes. Organisms most often have specific receptors for multiple types of siderophores, presumably to ensure adequate acquisition of the iron that is essential for their growth. Conjugation of drugs to synthetic hydroxamate or catechol siderophore components can facilitate active iron-transport-mediated drug delivery. While resistance to the siderophore-drug conjugates frequently occurs by selection of mutants deficient in the corresponding siderophore-selective outer membrane receptor, the mutants are less able to survive under iron-deficient conditions and in vivo. We anticipated that synthesis of mixed ligand siderophore-drug conjugates would allow active drug delivery by multiple iron receptor recognition and transport processes, further reducing the likelihood that resistant mutants would be viable.Results: Mixed ligand siderophore-drug conjugates were synthesized by combining hydroxamate and catechol components in a single compound that could chelate iron, and that also contained a covalent linkage to carbacephalosporins, as representative drugs. The new conjugates appear to be assimilated by multiple active iron-transport processes both in wild type microbes and in selected mutants that are deficient in some outer membrane iron-transport receptors.Conclusions: The concept of active iron-transport-mediated drug delivery can now be extended to drug conjugates that can enter the cell through multiple outer membrane receptors. Mutants that are resistant to such conjugates should be severely impaired in iron uptake, and therefore particularly prone to iron starvation. (C) Current Biology Ltd.