Novobiocin Enhances Polymyxin Activity by Stimulating Lipopolysaccharide Transport.
Novobiocin Enhances Polymyxin Activity by Stimulating Lipopolysaccharide Transport.
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DOI：
10.1021/jacs.8b02283
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发表时间：
2018-06-06
影响因子：
15
通讯作者：
Kahne D
中科院分区：
文献类型：
--
作者：
Mandler MD;Baidin V;Lee J;Pahil KS;Owens TW;Kahne D
革兰氏阴性细菌由于其不可穿透的外膜含有脂多糖(LPS)，因此很难用抗生素杀死。包括粘菌素在内的多粘菌素是治疗革兰氏阴性感染的最后手段。这些药物结合内毒素并破坏外膜；然而，它们的毒性限制了它们的用途。多粘菌素已被证明与许多抗生素有协同作用，包括抑制DNA旋转酶的新霉素，通过促进这些抗生素的外膜转运。最近，我们发现新生物素不仅能抑制DNA旋转酶，还能结合和刺激LptB，这是一种驱动内毒素转运的ATPase。在这里，我们报道了分离这两种活性的新生物素衍生物的合成。其中一个类似物保留了LptB刺激活性，但不能抑制DNA旋转酶。然而，这种本身无毒的类似物通过结合LptB和刺激内毒素转运来增强多粘菌素的致命性。因此，内毒素转运激动剂对新诺贝菌素-多粘菌素的协同作用有重要作用。我们还报道了其他新生物素类似物，它们对DNA旋转酶的抑制效果好于或等于新生物素，但与LptB结合得更好，因此具有更强的LptB刺激活性。当与多粘菌素联合使用时，这些化合物比新霉素更有效。针对旋转酶抑制和内毒素转运激动剂进行优化的Novobiocin类似物可能允许使用较低剂量的多粘菌素，从而提高其疗效和安全性。
Gram-negative bacteria are challenging to kill with antibiotics due to their impenetrable outer membrane containing lipopolysaccharide (LPS). The polymyxins, including colistin, are the drugs of last resort for treating Gram-negative infections. These drugs bind LPS and disrupt the outer membrane; however, their toxicity limits their usefulness. Polymyxin has been shown to synergize with many antibiotics including novobiocin, which inhibits DNA gyrase, by facilitating transport of these antibiotics across the outer membrane. Recently, we have shown that novobiocin not only inhibits DNA gyrase, but also binds and stimulates LptB, the ATPase that powers LPS transport. Here, we report the synthesis of novobiocin derivatives that separate these two activities. One analog retains LptB-stimulatory activity but is unable to inhibit DNA gyrase. This analog, which is not toxic on its own, nevertheless enhances the lethality of polymyxin by binding LptB and stimulating LPS transport. Therefore, LPS transport agonism contributes substantially to novobiocin-polymyxin synergy. We also report other novobiocin analogs that inhibit DNA gyrase better than or equal to novobiocin, but bind better to LptB and therefore have even greater LptB stimulatory activity. These compounds are more potent than novobiocin when used in combination with polymyxin. Novobiocin analogs optimized for both gyrase inhibition and LPS transport agonism may allow the use of lower doses of polymyxin, increasing its efficacy and safety.
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