Pharmaceutical Institute, Eberhard Karls-Universität Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany.
Int J Med Microbiol. 2014 Jan;304(1):31-6. doi: 10.1016/j.ijmm.2013.08.013. Epub 2013 Sep 4.
The aminocoumarins novobiocin, clorobiocin and coumermycin A1 are structurally related antibiotics produced by different Streptomyces strains. They are potent inhibitors of bacterial gyrase. Their binding sites and their mode of action differ from those of fluoroquinolones such as ciprofloxacin. Novobiocin has been introduced into clinical use against Staphylococcus aureus infections, and S. aureus gyrase is particularly sensitive to inhibition by aminocoumarins, while topoisomerase IV is much less sensitive. Modern genetic techniques have allowed the engineering of the producer strains, resulting in a diverse range of new aminocoumarins, including compounds which are more active than the natural antibiotics as well as a compound which is actively imported across the cell envelope of Gram-negative bacteria. A further group of aminocoumarins are the simocyclinones which bind simultaneously to two different sites of gyrase and show a completely new mode of inhibition. Both the simocyclinones and the "classical" aminocoumarins strongly inhibit the fluoroquinolone-induced activation of RecA and thereby the SOS response in S. aureus. Therefore, a combination of aminocoumarins and fluoroquinolones strongly reduced the risk of resistance development and may offer new prospects in anti-infective therapy.
氨基香豆素类抗生素新生霉素、氯柔红霉素和寇美菌素 A1 是由不同链霉菌菌株产生的结构相关的抗生素。它们是细菌拓扑异构酶 II 的强效抑制剂。它们的结合部位和作用方式与氟喹诺酮类药物（如环丙沙星）不同。新生霉素已被引入临床用于治疗金黄色葡萄球菌感染，金黄色葡萄球菌拓扑异构酶 II 对氨基香豆素类抗生素的抑制特别敏感，而拓扑异构酶 IV 的敏感性则低得多。现代遗传技术允许对产生菌进行工程改造，从而产生了一系列新的氨基香豆素类抗生素，包括比天然抗生素更具活性的化合物以及一种可主动穿过革兰氏阴性菌细胞膜的化合物。另一组氨基香豆素类抗生素是西蒙菌素，它同时结合拓扑异构酶 II 的两个不同部位，并显示出一种全新的抑制模式。西蒙菌素和“经典”氨基香豆素类抗生素都强烈抑制氟喹诺酮类药物诱导的 RecA 激活，从而抑制金黄色葡萄球菌中的 SOS 反应。因此，氨基香豆素类抗生素和氟喹诺酮类药物的联合使用大大降低了耐药性发展的风险，并可能为抗感染治疗提供新的前景。
