Collapsing the Proton Motive Force to Identify Synergistic Combinations against Staphylococcus aureus
Collapsing the Proton Motive Force to Identify Synergistic Combinations against Staphylococcus aureus
复制标题
DOI：
10.1016/j.chembiol.2013.07.006
复制
发表时间：
2013-09-19
影响因子：
--
通讯作者：
Brown, Eric D.
中科院分区：
文献类型：
--
作者：
Farha, Maya A.;Verschoor, Chris P.;Brown, Eric D.
由于毒性问题，细菌能量代谢的途径，如质子动力（PMF），在很大程度上仍未作为药物靶点进行探索。在这里，我们详细阐述了一个有条不紊的和系统的方法，针对PMF使用化学组合。我们从高通量筛选开始，以鉴定选择性地消散金黄色葡萄球菌中PMF的任一组分（Δ Psi或Δ pH）的分子。我们发现了六个扰动PMF，三个对抗Δ Psi和三个选择性消散Δ pH。Δ Psi的消散剂与Δ pH的消散剂的组合对耐甲氧西林S具有高度协同作用。金黄色。对哺乳动物细胞的细胞毒性分析表明，所观察到的协同作用的剂量节省效应可显著降低毒性。Δ Psi和Δ pH调节剂的发现和组合可能代表对抗微生物病原体的有希望的策略。
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, Delta Psi or Delta pH, in Staphylococcus aureus. We uncovered six perturbants of PMF, three that countered Delta Psi and three that selectively dissipated Delta pH. Combinations of dissipators of Delta Psi with dissipators of Delta pH 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 Delta Psi and Delta pH may represent a promising strategy for combating microbial pathogens.