Derivatives of Ribosome-Inhibiting Antibiotic Chloramphenicol Inhibit the Biosynthesis of Bacterial Cell Wall.
Derivatives of Ribosome-Inhibiting Antibiotic Chloramphenicol Inhibit the Biosynthesis of Bacterial Cell Wall.
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DOI：
10.1021/acsinfecdis.8b00078
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发表时间：
2018-07-13
影响因子：
5.3
通讯作者：
Fridman M
中科院分区：
文献类型：
--
作者：
Louzoun Zada S;Green KD;Shrestha SK;Herzog IM;Garneau-Tsodikova S;Fridman M
本文介绍了细菌翻译抑制抗生素氯霉素（CAM）的α，β-不饱和羰基衍生物的制备和评价。与母体抗生素相比，含有α，β-不饱和酮的两种化合物（1和4）对革兰氏阳性病原菌的抑制谱更宽，最小抑制浓度范围为2 ~ 32 μg/mL。有趣的是，与母体CAM不同，这些化合物不抑制细菌翻译。细胞壁肽聚糖的显微证据和代谢标记表明，化合物1和4通过抑制细胞壁肽聚糖生物合成的早期阶段对金黄色葡萄球菌细胞包膜造成广泛的损伤。与破坏膜的抗菌阳离子两亲化合物不同，这些化合物不能迅速渗透细菌膜。与母体抗生素CAM一样，化合物1和4对金黄色葡萄球菌具有抑菌作用。化合物1和4对永生化有核哺乳动物细胞具有细胞毒性；然而，两者都没有对哺乳动物红细胞造成可测量的膜损伤。这些数据表明，所报道的cam衍生抗菌药物为开发新型细菌细胞壁生物合成抑制抗生素提供了新的分子支架。
Here, we describe the preparation and evaluation of α,β-unsaturated carbonyl derivatives of the bacterial translation inhibiting antibiotic chloramphenicol (CAM). Compared to the parent antibiotic, two compounds containing α,β-unsaturated ketones (1 and 4) displayed a broader spectrum of activity against a panel of Gram-positive pathogens with a minimum inhibitory concentration range of 2–32 μg/mL. Interestingly, unlike the parent CAM, these compounds do not inhibit bacterial translation. Microscopic evidence and metabolic labeling of a cell wall peptidoglycan suggested that compounds 1 and 4 caused extensive damage to the envelope of Staphylococcus aureus cells by inhibition of the early stage of cell wall peptidoglycan biosynthesis. Unlike the effect of membrane-disrupting antimicrobial cationic amphiphiles, these compounds did not rapidly permeabilize the bacterial membrane. Like the parent antibiotic CAM, compounds 1 and 4 had a bacteriostatic effect on S. aureus. Both compounds 1 and 4 were cytotoxic to immortalized nucleated mammalian cells; however, neither caused measurable membrane damage to mammalian red blood cells. These data suggest that the reported CAM-derived antimicrobial agents offer a new molecular scaffold for development of novel bacterial cell wall biosynthesis inhibiting antibiotics.
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影响因子：
4.6
作者：
Bera, Smritilekha;Dhondikubeer, Ramesh;Schweizer, Frank
通讯作者：
Schweizer, Frank
影响因子：
7.3
作者：
Berkov-Zrihen Y;Green KD;Labby KJ;Feldman M;Garneau-Tsodikova S;Fridman M
通讯作者：
Fridman M
影响因子：
64.8
作者：
Schlünzen, F;Zarivach, R;Franceschi, F
通讯作者：
Franceschi, F
DOI：
10.1073/pnas.1008685107
发表时间：
2010-10-05
影响因子：
11.1
作者：
Bulkley, David;Innis, C. Axel;Steitz, Thomas A.
通讯作者：
Steitz, Thomas A.
影响因子：
3.4
作者：
Amslinger, Sabine
通讯作者：
Amslinger, Sabine