Solithromycin Inhibition of Protein Synthesis and Ribosome Biogenesis in Staphylococcus aureus, Streptococcus pneumoniae, and Haemophilus influenzae
Solithromycin Inhibition of Protein Synthesis and Ribosome Biogenesis in Staphylococcus aureus, Streptococcus pneumoniae, and Haemophilus influenzae
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索利霉素抑制金黄色葡萄球菌、肺炎链球菌和流感嗜血杆菌的蛋白质合成和核糖体生物发生
DOI：
10.1128/aac.02316-12
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发表时间：
2013
影响因子：
4.9
通讯作者：
W. S. Champney
中科院分区：
文献类型：
--
作者：
Ward Rodgers;Ashley D. Frazier;W. S. Champney
摘要抗生素耐药微生物的持续增加推动了对新的抗生素靶标和改进的抗微生物剂的研究。酮内酯是大环内酯类抗生素的半合成衍生物，其对某些耐药生物体有效。索利霉素（CEM-101）是一种新型氟酮内酯，具有更好的抗菌效果。该化合物与核糖体的50 S大亚基结合并抑制蛋白质生物合成。与其他酮内酯一样，它会损害细菌核糖体亚基的形成。在肺炎链球菌、金黄色葡萄球菌和流感嗜血杆菌菌株中检查了这种作用机制。索利霉素对肺炎链球菌、金黄色葡萄球菌和流感嗜血杆菌的细胞活力、蛋白质合成和生长速率的平均50%抑制浓度（IC 50）分别为7.5、40和125 ng/ml。在所有三种生物体中，50 S亚基的净形成减少，IC 50与上述相似。在索利霉素的IC 50下生长的细胞中，通过脉冲追踪标记程序测量的50 S亚基形成速率降低了75%。索利霉素也刺激了23 S rRNA的周转。索利霉素被发现是一种特别有效的抗菌剂，在这三种微生物中的IC 50与泰利霉素相当，并且显著优于阿奇霉素和克拉霉素。
ABSTRACT The continuing increase in antibiotic-resistant microorganisms is driving the search for new antibiotic targets and improved antimicrobial agents. Ketolides are semisynthetic derivatives of macrolide antibiotics, which are effective against certain resistant organisms. Solithromycin (CEM-101) is a novel fluoroketolide with improved antimicrobial effectiveness. This compound binds to the large 50S subunit of the ribosome and inhibits protein biosynthesis. Like other ketolides, it should impair bacterial ribosomal subunit formation. This mechanism of action was examined in strains of Streptococcus pneumoniae, Staphylococcus aureus, and Haemophilus influenzae. The mean 50% inhibitory concentrations (IC50s) for solithromycin inhibition of cell viability, protein synthesis, and growth rate were 7.5, 40, and 125 ng/ml for Streptococcus pneumoniae, Staphylococcus aureus, and Haemophilus influenzae, respectively. The net formation of the 50S subunit was reduced in all three organisms, with IC50s similar to those given above. The rates of 50S subunit formation measured by a pulse-chase labeling procedure were reduced by 75% in cells growing at the IC50 of solithromycin. Turnover of 23S rRNA was stimulated by solithromycin as well. Solithromycin was found to be a particularly effective antimicrobial agent, with IC50s comparable to those of telithromycin and significantly better than those of azithromycin and clarithromycin in these three microorganisms.