新型阿米洛利衍生物可抑制多种菌株和定子类型的细菌运动,bioRxiv - Microbiology

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新型阿米洛利衍生物可抑制多种菌株和定子类型的细菌运动
bioRxiv - Microbiology Pub Date : 2021-07-15 , DOI: 10.1101/2021.04.13.439105
MI Islam , JH Bae , T Ishida , P Ridone , J Lin , MJ Kelso , Y Sowa , BJ Buckley , MAB Baker

细菌鞭毛马达 (BFM) 是一种蛋白质复合物，赋予细胞运动性并有助于存活和毒力。BFM 由离子选择性膜蛋白复合物定子和直接连接到大灯丝的转子组成，用作螺旋桨。定子复合物将离子穿过膜与驱动电机旋转的扭矩耦合。驱动 BFM 旋转的最常见离子梯度是质子 (H+) 和钠离子 (Na+)。钠驱动的定子，如弧菌属的 PomAPomB 定子复合物中的那些，可以被钠通道抑制剂抑制，特别是被 phenamil，一种有效且广泛使用的抑制剂。然而，自发现phenamil以来，相对较少的新钠运动抑制剂被描述。在这项研究中，我们从先前报道的阿米洛利衍生物的小库中表征了两种可能的运动抑制剂 HM2-16F 和 BB2-50F。我们使用了三种方法：对系留细胞旋转的影响、对自由游动细菌的影响和对标记珠旋转的影响。我们发现 HM2-16F 和 BB2-50F 都停止了由 Na+ 马达驱动的系留细胞的旋转，与匹配浓度的 phenamil 相当，并且还可以停止由 H+ 马达驱动的系留细胞的旋转。存在和不存在定子时的珠粒测量证实，与苯胺的既定作用模式相反，这些化合物不会通过与定子的直接结合来抑制旋转。总体而言，HM2-16F 和 BB2-50F 在 Na+ 和 H+ 定子类型以及致病和非致病菌株中停止游动。

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Novel amiloride derivatives that inhibit bacterial motility across multiple strains and stator types

The bacterial flagellar motor (BFM) is a protein complex that confers motility to cells and contributes to survival and virulence. The BFM consists of stators that are ion-selective membrane protein complexes and a rotor that directly connects to a large filament, acting as a propeller. The stator complexes couple ion transit across the membrane to torque that drives rotation of the motor. The most common ion gradients that drive BFM rotation are protons (H+) and sodium ions (Na+). The sodium-powered stators, like those in the PomAPomB stator complex of Vibrio spp, can be inhibited by sodium channel inhibitors, in particular, by phenamil, a potent and widely used inhibitor. However, relatively few new sodium-motility inhibitors have been described since the discovery of phenamil. In this study, we characterised two possible motility inhibitors HM2-16F and BB2-50F from a small library of previously reported amiloride derivatives. We used three approaches: effect on rotation of tethered cells, effect on free swimming bacteria and effect on rotation of marker beads. We showed that both HM2-16F and BB2-50F stopped rotation of tethered cells driven by Na+ motors comparable to phenamil at matching concentrations, and could also stop rotation of tethered cells driven by H+ motors. Bead measurements in presence and absence of stators confirmed that the compounds did not inhibit rotation via direct association with the stator, in contrast to the established mode of action of phenamil. Overall, HM2-16F and BB2-50F stopped swimming in both Na+ and H+ stator types, and in pathogenic and non-pathogenic strains.

更新日期：2021-07-15

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