Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States.
Department of Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States.
J Med Chem. 2023 Jun 8;66(11):7553-7569. doi: 10.1021/acs.jmedchem.3c00398. Epub 2023 May 26.
We tested a series of SQ109 analogues against and , in addition to determining their uncoupling activity. We then investigated potential protein targets, involved in quinone and cell wall biosynthesis, using "rescue" experiments. There was little effect of menaquinone on growth inhibition by SQ109, but there were large increases in the IC of SQ109 and its analogues (up to 20×) on addition of undecaprenyl phosphate (Up), a homologue of the mycobacterial decaprenyl (C) diphosphate. Inhibition of an undecaprenyl diphosphate phosphatase, an ortholog of the mycobacterial phosphatase, correlated with cell growth inhibition, and we found that cell growth inhibition could be well predicted by using uncoupler and Up-rescue results. We also investigated whether SQ109 was metabolized inside , finding only a single metabolite, previously shown to be inactive. The results are of general interest since they help explain the mechanism of SQ109 in mycobacteria.
我们测试了一系列 SQ109 类似物对 和 的抑制作用，此外还测定了它们的解偶联活性。然后，我们使用“挽救”实验研究了与醌和细胞壁生物合成相关的潜在蛋白靶标。甲萘醌对 SQ109 抑制生长的影响很小，但在添加十一碳烯基磷酸（Up）时，SQ109 及其类似物的 IC 值（高达 20 倍）有了大幅增加，Up 是分枝杆菌脱乙酰基（C）二磷酸的同系物。十一碳烯基二磷酸磷酸酶的抑制作用与细胞生长抑制相关，我们发现使用解偶联剂和 Up 挽救实验结果可以很好地预测细胞生长抑制。我们还研究了 SQ109 是否在细胞内代谢，只发现了一种先前显示为无活性的代谢产物。这些结果具有普遍意义，因为它们有助于解释 SQ109 在分枝杆菌中的作用机制。
