Ghosh M, Miller M J
Department of Chemistry and Biochemistry, University of Notre Dame, IN 46556, USA.
Bioorg Med Chem. 1996 Jan;4(1):43-8. doi: 10.1016/0968-0896(95)00161-1.
The first antibiotic conjugates of vancomycin (1) and siderophore analogues containing spermidine-based catechol ligands (conjugate 11) as well as mixed catechol and hydroxamate ligands (conjugate 13) are described. The design of the conjugates was based on the earlier observation that conjugation of siderophore components to beta-lactam antibiotics induced active iron transport-mediated drug delivery. The novel conjugates (11 and 13) were synthesized by selective acylation of the primary amino group of 1. Preliminary biological studies indicated that siderophore modified vancomycins lost some activity (4- to 16-fold) against Gram-positive bacteria relative to vancomycin itself, and were generally similar to vancomycin in activity against Gram-negative bacteria under iron-sufficient conditions. However, under iron-depleted conditions which mimic human serum, conjugate 11 displayed enhanced antibacterial activity against an antibiotic hypersensitive strain of Pseudomonas aeruginosa.
描述了万古霉素（1）与含有基于亚精胺的儿茶酚配体的铁载体类似物（缀合物11）以及混合的儿茶酚和异羟肟酸酯配体（缀合物13）的首批抗生素缀合物。缀合物的设计基于早期的观察结果，即铁载体成分与β-内酰胺抗生素的缀合诱导了活性铁转运介导的药物递送。新型缀合物（11和13）通过对1的伯氨基进行选择性酰化反应合成。初步生物学研究表明，相对于万古霉素本身，铁载体修饰的万古霉素对革兰氏阳性菌的活性丧失了一些（4至16倍），并且在铁充足的条件下，其对革兰氏阴性菌的活性通常与万古霉素相似。然而，在模拟人血清的缺铁条件下，缀合物11对铜绿假单胞菌的抗生素超敏菌株显示出增强的抗菌活性。
