Biosynthetic Studies and Genetic Engineering of Pactamycin Analogs with Improved Selectivity toward Malarial Parasites
Biosynthetic Studies and Genetic Engineering of Pactamycin Analogs with Improved Selectivity toward Malarial Parasites
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DOI：
10.1016/j.chembiol.2011.01.016
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发表时间：
2011-04-22
影响因子：
--
通讯作者：
Mahmud, Taifo
中科院分区：
文献类型：
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作者：
Lu, Wanli;Roongsawang, Niran;Mahmud, Taifo
朴大霉素是功能最密集的氨基环醇抗生素之一，具有显着的抗菌、抗肿瘤、抗病毒和抗疟原虫活性，但其作为临床药物的开发因其广泛的细胞毒性而受到阻碍。由于其化学结构的复杂性，使用合成有机化学通过结构修饰来调节生物活性的努力一直很困难。然而，通过广泛的生物合成研究和基因工程，我们能够生产出具有强大抗疟活性的巴塔霉素类似物，但缺乏显着的抗菌活性，并且对哺乳动物细胞的毒性比巴塔霉素低约10-30倍。结果表明，独特的核糖体结合选择性或新的作用机制可能参与其疟原虫生长抑制，这可能导致新的抗疟药物的发现和疟疾寄生虫内新分子靶点的鉴定。
Pactamycin, one of the most densely functionalized aminocyclitol antibiotics, has pronounced antibacterial, antitumor, antiviral, and antiplasmodial activities, but its development as a clinical drug was hampered by its broad cytotoxicity. Efforts to modulate the biological activity by structural modifications using synthetic organic chemistry have been difficult because of the complexity of its chemical structure. However, through extensive biosynthetic studies and genetic engineering, we were able to produce analogs of pactamycin that show potent antimalarial activity, but lack significant antibacterial activity, and are about 10-30 times less toxic than pactamycin toward mammalian cells. The results suggest that distinct ribosomal binding selectivity or new mechanism(s) of action may be involved in their plasmodial growth inhibition, which may lead to the discovery of new antimalarial drugs and identification of new molecular targets within malarial parasites.