PURIFICATION, TOXICITY, AND ANTIENDOTOXIN ACTIVITY OF POLYMYXIN-B NONAPEPTIDE
PURIFICATION, TOXICITY, AND ANTIENDOTOXIN ACTIVITY OF POLYMYXIN-B NONAPEPTIDE
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DOI：
10.1128/aac.33.9.1428
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发表时间：
1989-09-01
影响因子：
4.9
通讯作者：
PARRILLO, JE
中科院分区：
文献类型：
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作者：
DANNER, RL;JOINER, KA;PARRILLO, JE
多粘菌素B是一种毒性相对较大的抗生素，具有强大的内毒素中和特性，可能有助于作为革兰氏阴性脓毒症的辅助治疗。多粘菌素B九肽(脱酰化多粘菌素B)没有抗生素活性，但仍具有破坏革兰氏阴性细菌外膜的能力。为了评价该衍生物的潜在治疗作用，我们制备了纯化的多粘菌素B九肽，进行了动物体内毒性试验，并评价了其体外抗内毒素活性。通过检测多粘菌素B九肽阻断脂多糖诱导的中性粒细胞释放毒性氧自由基的能力来评价其抗内毒素的有效性。在体内，在1.5和3.0 mg/kg剂量下，多粘菌素B九肽没有表现出多粘菌素B硫酸盐所观察到的神经肌肉阻断、神经毒性或肾毒性作用。多粘菌素B和多粘菌素B九肽均以浓度方式抑制脂多糖诱导的中性粒细胞启动，但母体化合物多粘菌素B的抑制作用在重量基础上是脂多糖的63倍。然而，当两种化合物在脂多糖-中性粒细胞孵育开始后加入时，其抑制活性迅速减弱。我们的结论是，多粘菌素B的毒性比多粘菌素B小，在所测试的剂量下，没有母体化合物的神经毒性和肾毒性。多粘菌素B九肽保留了多粘菌素B的抗内毒素活性，但效力要弱得多。这些发现表明，这些化合物阻止了中性粒细胞启动过程的早期步骤，可能是脂多糖附着或插入中性粒细胞膜。
Polymyxin B, a relatively toxic antibiotic, has potent endotoxin-neutralizing properties that may be beneficial as adjunctive therapy in gram-negative sepsis. Polymyxin B nonapeptide (deacylated polymyxin B) is devoid of antibiotic activity but retains the capacity to disorganize the outer membrane of gram-negative bacteria. To evaluate the potential therapeutic usefulness of this derivative, we produced purified polymyxin B nonapeptide, tested its in vivo toxicity in animals, and evaluated its in vitro antiendotoxin activity. Effectiveness as an antiendotoxin agent was assessed by examining the ability of polymyxin B nonapeptide to block the enhanced release of toxic oxygen radicals induced by lipopolysaccharide in human neutrophils (priming). In vivo, at doses of 1.5 and 3.0 mg/kg, polymyxin B nonapeptide did not exhibit the neuromuscular blocking, neurotoxic, or nephrotoxic effects that were observed with polymyxin B sulfate. Both polymyxin B and polymyxin B nonapeptide inhibited lipopolysaccharide-induced neutrophil priming in a concentration manner, but the parent compound, polymyxin B, was 63 times more effective on a weight basis. The inhibitory activity of both compounds, however, diminished rapidly when they were added after the start of the lipopolysaccharide-neutrophil incubation. We conclude that polymyxin B nonapeptide is less toxic than polymyxin B and, at the doses tested, lacks the neurotoxicity and nephrotoxicity of the parent compound. Polymyxin B nonapeptide retains the antiendotoxin activity of polymyxin B but is much less potent. The findings suggest that these compounds block an early step in the neutrophil priming process, possibly lipopolysaccharide attachment to or insertion into the neutrophil membrane.