小柯机器人

美国哈佛大学Daniel Kahne和美国哈佛医学院Andrew C. Kruse共同合作，近期取得重要工作进展。他们研究发现了一种新型抗生素能在膜间转运蛋白中捕获脂多糖。相关研究成果2024年1月3日在线发表于《自然》杂志上。

据介绍，革兰氏阴性菌非常难杀死，因为它们的细胞质膜被一层外膜包围，阻止了大多数抗生素的进入。外膜的不可穿透性是由于其小叶中存在一种名为脂多糖（LPS）的大型两亲性糖脂。外膜的组装需要LPS通过从细胞质膜到细胞表面的蛋白质桥运输。维持外膜完整性对细菌细胞的生存能力至关重要，其破坏会增加对其它抗生素的易感性。因此，人们一直在寻找形成这种转运蛋白的七种脂多糖转运蛋白的抑制剂。最近发现了一类针对不动杆菌LPS转运机制的新抗生素。

使用结构、生物化学和遗传学方法，研究人员表明这些抗生素捕获了LPS转运蛋白的底物结合构象，从而阻止了这台机器。抑制剂通过识别由Lpt转运蛋白及其LPS底物组成的复合结合位点来实现这一点。

总之，这一发现确定了一种不寻常的脂质转运抑制机制，揭示了Lpt转运蛋白的可药用构象，并为将这类抗生素扩展到其它革兰氏阴性病原体提供了基础。

附：英文原文

Title: A new antibiotic traps lipopolysaccharide in its intermembrane transporter

Author: Pahil, Karanbir S., Gilman, Morgan S. A., Baidin, Vadim, Clairfeuille, Thomas, Mattei, Patrizio, Bieniossek, Christoph, Dey, Fabian, Muri, Dieter, Baettig, Remo, Lobritz, Michael, Bradley, Kenneth, Kruse, Andrew C., Kahne, Daniel

Issue&Volume: 2024-01-03

Abstract: Gram-negative bacteria are extraordinarily difficult to kill because their cytoplasmic membrane is surrounded by an outer membrane that blocks the entry of most antibiotics. The impenetrable nature of the outer membrane is due to the presence of a large, amphipathic glycolipid called lipopolysaccharide (LPS) in its outer leaflet1. Assembly of the outer membrane requires transport of LPS across a protein bridge that spans from the cytoplasmic membrane to the cell surface. Maintaining outer membrane integrity is essential for bacterial cell viability, and its disruption can increase susceptibility to other antibiotics2,3,4,5,6. Thus, inhibitors of the seven lipopolysaccharide transport (Lpt) proteins that form this transenvelope transporter have long been sought. A new class of antibiotics that targets the LPS transport machine in Acinetobacter was recently identified. Here, using structural, biochemical and genetic approaches, we show that these antibiotics trap a substrate-bound conformation of the LPS transporter that stalls this machine. The inhibitors accomplish this by recognizing a composite binding site made up of both the Lpt transporter and its LPS substrate. Collectively, our findings identify an unusual mechanism of lipid transport inhibition, reveal a druggable conformation of the Lpt transporter and provide the foundation for extending this class of antibiotics to other Gram-negative pathogens.

DOI: 10.1038/s41586-023-06799-7

Source: https://www.nature.com/articles/s41586-023-06799-7

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
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