MurF Inhibitors with Antibacterial Activity: Effect on Muropeptide Levels
MurF Inhibitors with Antibacterial Activity: Effect on Muropeptide Levels
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DOI：
10.1128/aac.00166-09
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发表时间：
2009-08-01
影响因子：
4.9
通讯作者：
Bush, Karen
中科院分区：
文献类型：
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作者：
Baum, Ellen Z.;Crespo-Carbone, Steven M.;Bush, Karen
MURF催化细菌细胞壁合成的最后一步，是细菌生存所必需的。我们之前的研究使用了MURF抑制剂的药效团模型来确定具有更好性能的其他抑制剂。我们现在介绍两个这样的抑制剂的特征，二芳基喹啉DQ1和DQ2。DQ1对大肠杆菌MURF(50%抑菌浓度，24 mU M)有抑制作用，对脂多糖(LPS)缺陷的大肠杆菌和对多粘菌素B具有通透性的野生型大肠杆菌有一定的抑制作用(MIC，8~16 mU g/ml)。此外，DQ2还显示出对革兰氏阳性菌(MICs，8至16mU g/ml)的活性，包括甲氧西林(甲氧西林)敏感和耐药的金黄色葡萄球菌分离株，以及万古霉素敏感和耐药的粪肠球菌和粪肠球菌分离株。用~gt；=2xMIC的DQ1处理内毒素缺陷的大肠杆菌细胞，与对照组相比，MURF底物的积累增加了75倍，MURF产物的量下降了70%，最终细胞裂解，这与细菌内MURF的抑制一致。DQ2处理金黄色葡萄球菌对MURF底物和产物数量的影响相似。在第一季的较低水平(
MurF catalyzes the last cytoplasmic step of bacterial cell wall synthesis and is essential for bacterial survival. Our previous studies used a pharmacophore model of a MurF inhibitor to identify additional inhibitors with improved properties. We now present the characterization of two such inhibitors, the diarylquinolines DQ1 and DQ2. DQ1 inhibited Escherichia coli MurF (50% inhibitory concentration, 24 mu M) and had modest activity (MICs, 8 to 16 mu g/ml) against lipopolysaccharide (LPS)-defective E. coli and wild-type E. coli rendered permeable with polymyxin B nonapeptide. DQ2 additionally displayed activity against gram-positive bacteria (MICs, 8 to 16 mu g/ml), including methicillin (meticillin)-susceptible and-resistant Staphylococcus aureus isolates and vancomycin-susceptible and-resistant Enterococcus faecalis and Enterococcus faecium isolates. Treatment of LPS-defective E. coli cells with >= 2 x MIC of DQ1 resulted in a 75-fold-greater accumulation of the MurF substrate compared to the control, a 70% decline in the amount of the MurF product, and eventual cell lysis, consistent with the inhibition of MurF within bacteria. DQ2 treatment of S. aureus resulted in similar effects on the MurF substrate and product quantities. At lower levels of DQ1 (