Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
FASEB J. 2019 Mar;33(3):3180-3189. doi: 10.1096/fj.201801628R. Epub 2018 Oct 25.
The bacterial mechanosensitive channel of large conductance (MscL) normally functions as an emergency release valve discharging cytoplasmic solutes upon osmotic stress. Opening the large pore of MscL inappropriately is detrimental to the cell, and thus it has been speculated to be a potential antibiotic target. Although MscL is one of the best studied mechanosensitive channels, no chemical that influenced bacterial growth by modulating MscL is known. We therefore used a high-throughput screen to identify compounds that slowed growth in an MscL-dependent manner. We characterized 2 novel sulfonamide compounds identified in the screen. We demonstrated that, although both increase MscL gating, one of these compounds does not work through the folate pathway, as other antimicrobial sulfonamides; indeed, the sulfonamide portion of the compound is not needed for activity. The only mode of action appears to be MscL activation. The binding pocket is where an α-helix runs along the cytoplasmic membrane and interacts with a neighboring subunit; analogous motifs have been observed in several prokaryotic and eukaryotic channels. The data not only demonstrate that MscL is a viable antibiotic target, but also give insight into the gating mechanisms of MscL, and they may have implications for developing agonists for other channels.-Wray, R., Iscla, I., Kovacs, Z., Wang, J., Blount, P. Novel compounds that specifically bind and modulate MscL: insights into channel gating mechanisms.
细菌的大电导机械敏感通道（MscL）通常在渗透胁迫时作为细胞质溶质的紧急释放阀起作用。不恰当地打开 MscL 的大孔对细胞是有害的，因此它被推测为一种潜在的抗生素靶标。尽管 MscL 是研究得最好的机械敏感通道之一，但目前还没有通过调节 MscL 来影响细菌生长的化学物质。因此，我们使用高通量筛选来鉴定以依赖 MscL 的方式减缓生长的化合物。我们对筛选中鉴定出的 2 种新型磺胺类化合物进行了表征。我们证明，尽管这两种化合物都增加了 MscL 的门控，但其中一种化合物不像其他抗菌磺胺类药物那样通过叶酸途径起作用；实际上，该化合物的磺胺部分对于活性不是必需的。唯一的作用方式似乎是 MscL 激活。结合口袋是一个α-螺旋沿着细胞质膜运行并与相邻亚基相互作用的地方；在几种原核和真核通道中都观察到了类似的模体。这些数据不仅证明 MscL 是一个可行的抗生素靶标，而且深入了解了 MscL 的门控机制，并且它们可能对开发其他通道的激动剂具有意义。-Wray，R.，Iscla，I.，Kovacs，Z.，Wang，J.，Blount，P.。特异性结合和调节 MscL 的新型化合物：对通道门控机制的深入了解。
