Dolence E K, Minnick A A, Lin C E, Miller M J, Payne S M
Department of Chemistry and Biochemistry, University of Notre Dame, Indiana 46556.
J Med Chem. 1991 Mar;34(3):968-78. doi: 10.1021/jm00107a014.
N5-Acetyl-N5-hydroxy-L-ornithyl-N5-acetyl-N5-hydroxy-L-ornithyl-N5-acety l- N5-hydroxy-L-ornithine, the functionally instrumental component of the albomycins and ferrichromes, has been incorporated as a "carrier" substructure into both carbacephalosporin and oxamazin type beta-lactam antibiotics. The previously synthesized protected version of this tripeptide (14) was coupled with various beta-lactam analogues 17, 19, 24, and 25 to give protected conjugates 21, 22, 26, and 27. Final deprotection by hydrogenolysis provided the deprotected siderophore-beta-lactam antibiotic conjugates 1-4. The growth-promoting ability of each has been evaluated using either the siderophore-deficient mutant Shigella flexneri SA 100 or S. flexneri SA240 (SA 100 iucD:Tn5). Measurement of the growth-promoting activity using two isogenic Escherichia coli strains differing only in the presence or absence of fhuA (hydroxamate ferrichrome receptor) suggests uptake by the hydroxamate iron-transport system. The antibacterial activity of these conjugates has been investigated, and the potential for use of the ferrichrome iron-transport system as a means of drug delivery is discussed.
N5-乙酰基-N5-羟基-L-鸟氨酰-N5-乙酰基-N5-羟基-L-鸟氨酰-N5-乙酰基-N5-羟基-L-鸟氨酸是阿波霉素和铁载体色素的功能活性成分，已作为“载体”亚结构被引入碳头孢菌素和恶嗪型β-内酰胺抗生素中。该三肽先前合成的保护形式（14）与各种β-内酰胺类似物17、19、24和25偶联，得到保护的缀合物21、22、26和27。通过氢解进行最终脱保护，得到脱保护的铁载体-β-内酰胺抗生素缀合物1-4。使用铁载体缺陷型突变体弗氏志贺菌SA 100或弗氏志贺菌SA240（SA 100 iucD:Tn5）评估了每种化合物的促生长能力。使用仅在是否存在fhuA（异羟肟酸铁载体色素受体）方面存在差异的两株同基因大肠杆菌菌株测量促生长活性，表明其通过异羟肟酸铁转运系统摄取。研究了这些缀合物的抗菌活性，并讨论了利用铁载体色素铁转运系统作为药物递送手段的潜力。
