Miller M J, McKee J A, Minnick A A, Dolence E K
Department of Chemistry and Biochemistry, University of Notre Dame, Indiana 46556.
Biol Met. 1991;4(1):62-9. doi: 10.1007/BF01135559.
The use of conjugates of microbial iron chelators (siderophores) and antibiotics for illicit transport of antibiotics into cells is a potentially powerful method for the rational design of therapeutic agents. The structural complexity of most natural siderophores has impeded progress in this area. Described here are the design, syntheses and preliminary biological studies of several siderophore-beta-lactam antibiotic conjugates. Both hydroxamic-acid-based and catechol-based conjugates with and without amino acid spacers to carbacephalosporins were synthesized and demonstrated to be effective inhibitors of Escherichia coli X580. Mutant selection was noted for each class of conjugates. Mutants selected from exposure of the E. coli to the hydroxamate conjugates were susceptible to the catechol conjugates and vice versa. Combinations of hydroxamate- and catechol-carbacephalosporin conjugates were most effective inhibitors of E. coli X580.
利用微生物铁螯合剂（铁载体）与抗生素的缀合物将抗生素非法转运到细胞内，是一种用于合理设计治疗剂的潜在有效方法。大多数天然铁载体的结构复杂性阻碍了该领域的进展。本文描述了几种铁载体-β-内酰胺抗生素缀合物的设计、合成及初步生物学研究。合成了带有和不带有连接到碳头孢菌素的氨基酸间隔基的基于异羟肟酸和基于儿茶酚的缀合物，并证明它们是大肠杆菌X580的有效抑制剂。注意到每类缀合物都存在突变体选择现象。从大肠杆菌暴露于异羟肟酸缀合物中选择出的突变体对儿茶酚缀合物敏感，反之亦然。异羟肟酸-和儿茶酚-碳头孢菌素缀合物的组合是大肠杆菌X580最有效的抑制剂。
