Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
ACS Infect Dis. 2020 Jul 10;6(7):1796-1806. doi: 10.1021/acsinfecdis.0c00056. Epub 2020 May 6.
Twenty-three polymyxin analogs with variations at nine amino acid positions were synthesized and assessed for antimicrobial activity and renal cytotoxicity. Compounds , , , and (MIC = 0.125-4 μg/mL) had similar or stronger activities against susceptible and drug-resistant strains of , , , and compared to polymyxin B (MIC = 1-2 μg/mL). Most synthesized compounds (50% cytotoxic concentration, CC ≥ 200 μg/mL) exhibited lower cytotoxicity than polymyxin B (CC = 99 ± 6 μg/mL). Polymyxin S showed high plasma stability and strong efficacy in a mouse systemic infection model (ED = 0.9 mg/kg) against NDM-1-producing , suggesting that it is a potential candidate for drug development. The activity and cytotoxicity results indicated that the amino acids at positions 2, 3, 6, and 7 might be replaced. Effects on activity and cytotoxicity linked to changes in the number of positively charged amino acids varied among different cyclopeptide skeletons, but the underlying mechanisms are unknown.
合成了 23 种在九个氨基酸位置上具有变异的多粘菌素类似物，并评估了它们的抗菌活性和肾毒性。与多粘菌素 B（MIC = 1-2 μg/mL）相比，化合物 、 、 、 （MIC = 0.125-4 μg/mL）对敏感和耐药的 、 、 、 株具有相似或更强的活性。与多粘菌素 B（CC = 99 ± 6 μg/mL）相比，大多数合成化合物（50%细胞毒性浓度，CC ≥ 200 μg/mL）的细胞毒性较低。多粘菌素 S 在携带 NDM-1 的 系统性感染模型中具有高血浆稳定性和强大的疗效（ED = 0.9 mg/kg），表明它是一种有潜力的药物开发候选物。活性和细胞毒性结果表明，位置 2、3、6 和 7 的氨基酸可能被取代。活性和细胞毒性变化与正电荷氨基酸数量变化之间的关系因不同环肽骨架而异，但潜在机制尚不清楚。
