Farha Maya A, Verschoor Chris P, Bowdish Dawn, Brown Eric D
Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8N 3Z5, Canada; Michael G. DeGroote Institute of Infectious Disease Research, McMaster University, Hamilton, ON L8N 3Z5, Canada.
Chem Biol. 2013 Sep 19;20(9):1168-78. doi: 10.1016/j.chembiol.2013.07.006. Epub 2013 Aug 22.
Pathways of bacterial energy metabolism, such as the proton motive force (PMF), have largely remained unexplored as drug targets, owing to toxicity concerns. Here, we elaborate on a methodical and systematic approach for targeting the PMF using chemical combinations. We began with a high-throughput screen to identify molecules that selectively dissipate either component of the PMF, ΔΨ or ΔpH, in Staphylococcus aureus. We uncovered six perturbants of PMF, three that countered ΔΨ and three that selectively dissipated ΔpH. Combinations of dissipators of ΔΨ with dissipators of ΔpH were highly synergistic against methicillin-resistant S. aureus. Cytotoxicity analyses on mammalian cells revealed that the dose-sparing effect of the observed synergies could significantly reduce toxicity. The discovery and combination of modulators of ΔΨ and ΔpH may represent a promising strategy for combating microbial pathogens.
由于毒性问题，诸如质子动力（PMF）等细菌能量代谢途径在很大程度上仍未被探索作为药物靶点。在此，我们阐述了一种使用化学组合靶向PMF的系统方法。我们首先进行了高通量筛选，以鉴定在金黄色葡萄球菌中选择性消除PMF的任一组成部分（ΔΨ或ΔpH）的分子。我们发现了六种PMF扰动剂，其中三种对抗ΔΨ，三种选择性地消除ΔpH。ΔΨ消散剂与ΔpH消散剂的组合对耐甲氧西林金黄色葡萄球菌具有高度协同作用。对哺乳动物细胞的细胞毒性分析表明，观察到的协同作用的剂量节省效应可显著降低毒性。ΔΨ和ΔpH调节剂的发现与组合可能代表了对抗微生物病原体的一种有前景的策略。
