Department of Physiology, UT Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, USA.
Division of Chemistry and Chemical Engineering 114-96, Howard Hughes Medical Institute, California Institute of Technology, Pasadena, CA, USA.
Mol Microbiol. 2019 Sep;112(3):896-905. doi: 10.1111/mmi.14325. Epub 2019 Jun 8.
The bacterial MscL channel normally functions as an emergency release valve discharging cytoplasmic solutes upon osmotic stress. The channel opens and passes molecules up to 30 Å and its pore is the largest of any gated channel. Opening the MscL pore inappropriately is detrimental to the bacterial cell, suggesting MscL as a potential novel drug target. A small-molecule compound, 011A, has been shown to increase sensitivity of the Escherichia coli MscL channel, slow growth, and even decrease viability of quiescent cultures. The mscL gene is highly conserved and found in the vast majority of bacterial species, including pathogens. Here, we test the hypothesis that 011A can influence the growth and viability of other bacterial species, specifically Staphylococcus aureus and Mycobacterium smegmatis, in a MscL-dependent manner. Furthermore, we demonstrate that the 011A compound can increase potency of other antibiotics, presumably by permeabilizing the membrane and allowing easier access of the antibiotic into the cytoplasm. Thus, MscL activators have potential as novel broad-spectrum antibiotics or adjuvants that work with antibiotics to selectively allow passage across bacterial membranes.
细菌 MscL 通道通常作为应急释放阀在渗透胁迫时排出细胞质溶质。该通道打开并允许分子量高达 30Å 的分子通过，其孔径是所有门控通道中最大的。不恰当地打开 MscL 孔对细菌细胞是有害的，这表明 MscL 是一个有潜力的新型药物靶点。一种小分子化合物 011A 已被证明能增加大肠杆菌 MscL 通道的敏感性，减缓生长速度，甚至降低静止培养物的活力。mscL 基因高度保守，存在于绝大多数细菌物种中，包括病原体。在这里，我们检验了这样一个假设，即 011A 可以以 MscL 依赖性的方式影响其他细菌物种（金黄色葡萄球菌和耻垢分枝杆菌）的生长和活力。此外，我们证明 011A 化合物可以增加其他抗生素的效力，可能是通过使膜通透性增加，使抗生素更容易进入细胞质。因此，MscL 激活剂具有作为新型广谱抗生素或佐剂的潜力，与抗生素一起选择性地允许穿过细菌膜。
