Bycroft B W, Lockey P M, Penrose A, Grout R J, Williams P
Department of Pharmaceutical Sciences, The University, Nottingham, United Kingdom.
Antimicrob Agents Chemother. 1989 Sep;33(9):1516-21. doi: 10.1128/AAC.33.9.1516.
N-Formyl dipeptide conjugates of ampicillin and amoxicillin related to the chemotactic peptide N-formyl-L-methionyl-L-leucyl-L-phenylalanine were synthesized and assessed for antibacterial activity and affinity for the chemotactic peptide receptor of differentiated human promyelocytic leukemia (HL-60) cells. The conjugates and parent beta-lactam antibiotics showed similar antibacterial activities against Escherichia coli and Staphylococcus aureus. The affinity of each conjugate for the chemotactic peptide receptor was determined in a competitive binding assay, using 3H-labeled N-formyl-L-methionyl-L-leucyl-L-phenylalanine. All conjugates bound to the receptor, but with affinities ranging from 1/3 to 1/100 that of the tritiated substrate. There was good correlation between receptor affinity and stimulation of chemotaxis. The peptide-antibiotic conjugates also stimulated the oxidative metabolism of the HL-60 cells by inducing the production of superoxide and hydrogen peroxide as determined by Luminol- and Lucigenin-enhanced chemiluminescence. These conjugates, based on N-formyl-L-methionyl-L-leucyl-L-phenylalanine, thus combine both potent antibacterial and immunostimulatory properties within the same molecule.
合成了与趋化肽N-甲酰-L-蛋氨酰-L-亮氨酰-L-苯丙氨酸相关的氨苄西林和阿莫西林的N-甲酰二肽缀合物，并评估了它们的抗菌活性以及对分化的人早幼粒细胞白血病（HL-60）细胞趋化肽受体的亲和力。这些缀合物和母体β-内酰胺抗生素对大肠杆菌和金黄色葡萄球菌显示出相似的抗菌活性。使用3H标记的N-甲酰-L-蛋氨酰-L-亮氨酰-L-苯丙氨酸，通过竞争性结合试验测定了每种缀合物对趋化肽受体的亲和力。所有缀合物均与受体结合，但其亲和力范围为氚化底物的1/3至1/100。受体亲和力与趋化作用的刺激之间存在良好的相关性。肽-抗生素缀合物还通过诱导超氧化物和过氧化氢的产生刺激了HL-60细胞的氧化代谢，这是通过鲁米诺和光泽精增强的化学发光测定的。因此，基于N-甲酰-L-蛋氨酰-L-亮氨酰-L-苯丙氨酸的这些缀合物在同一分子中兼具强大的抗菌和免疫刺激特性。
