Minnick A A, McKee J A, Dolence E K, Miller M J
Department of Chemistry and Biochemistry, University of Notre Dame, Indiana 46556.
Antimicrob Agents Chemother. 1992 Apr;36(4):840-50. doi: 10.1128/AAC.36.4.840.
Peptides containing residues of N5-acetyl-N5-hydroxy-L-ornithine were evaluated as potential artificial siderophores of beta-lactam-hypersusceptible Escherichia coli X580. Only those peptides which were capable of forming a hexadentate complex around ferric iron, which is analogous to the natural siderophore ferrichrome, were able to reverse the growth inhibition effects of the ferric iron chelator ethylenediamine di(o-hydroxyphenylacetic acid). A synthetic bis(catechol) spermidine derivative, similar to the natural siderophores enterobactin and agrobactin, also exhibited siderophore activity with this strain. Conjugation of the N5-acetyl-N5-hydroxy-L-ornithine tripeptide and the bis(catechol) siderophore to the potent carbacephalosporin loracarbef and closely related analogs provided compounds which exhibited antibacterial activity against E. coli X580. As was observed with the naturally occurring albomycins, the initial bactericidal effect was followed by the appearance of survivors that were resistant to the test compound. An enhanced killing effect was observed when the parent was incubated simultaneously with hydroxamate and catechol siderophore-antibiotic conjugates. Natural and synthetic siderophore growth promotion experiments with survivors resistant to the conjugates strongly suggested that disabled ferrichrome and enterobactin-catechol assimilation mechanisms may be responsible for the observed resistance. One isolated survivor was postulated to be a tonB mutant. The antibacterial activities of the described siderophore-carbacephalosporin conjugates appear to be related to an iron transport assimilation mechanism and would not have been detected during routine MIC testing procedures.
含有N5-乙酰基-N5-羟基-L-鸟氨酸残基的肽被评估为β-内酰胺超敏性大肠杆菌X580的潜在人工铁载体。只有那些能够在三价铁周围形成六齿络合物（类似于天然铁载体铁色素）的肽，才能逆转三价铁螯合剂乙二胺二（邻羟基苯乙酸）的生长抑制作用。一种类似于天然铁载体肠杆菌素和土壤杆菌素的合成双（儿茶酚）亚精胺衍生物，对该菌株也表现出铁载体活性。将N5-乙酰基-N5-羟基-L-鸟氨酸三肽和双（儿茶酚）铁载体与强效碳头孢烯类洛拉卡贝及其密切相关类似物进行缀合，得到了对大肠杆菌X580具有抗菌活性的化合物。正如在天然存在的白霉素中观察到的那样，最初的杀菌作用之后出现了对测试化合物具有抗性的存活菌。当亲本与异羟肟酸和儿茶酚铁载体-抗生素缀合物同时孵育时，观察到增强的杀伤效果。对缀合物具有抗性的存活菌进行的天然和合成铁载体促进生长实验强烈表明，铁色素和肠杆菌素-儿茶酚同化机制失活可能是观察到的抗性的原因。推测一个分离出的存活菌是tonB突变体。所述铁载体-碳头孢烯缀合物的抗菌活性似乎与铁转运同化机制有关，在常规MIC测试程序中不会检测到。
