Chemistry Department, Institute for Drug Discovery, Purdue University, West Lafayette, IN, 47907, USA; Graduate Program in Biochemistry, University of Maryland, College Park, MD, 20742, USA.
Chemistry Department, Institute for Drug Discovery, Purdue University, West Lafayette, IN, 47907, USA.
Eur J Med Chem. 2018 Jul 15;155:797-805. doi: 10.1016/j.ejmech.2018.06.023. Epub 2018 Jun 15.
Various reports of multidrug-resistant bacteria that are immune to all available FDA-approved drugs demand the development of novel chemical scaffolds as antibiotics. From screening a chemical library, we identified compounds with antibacterial activity. The most potent compounds, F6-5 and F6, inhibited growth of various drug-resistant Gram-positive bacterial pathogens at concentrations ranging from 1 μg/mL to 2 μg/mL. Both compounds were active against clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-intermediate and vancomycin-resistant S. aureus (VISA and VRSA respectively) and vancomycin-resistant Enterococcus faecalis (VRE). Resistance generation experiments revealed that MRSA could develop resistance to the antibiotic ciprofloxacin but not to F6. Excitingly, F6 was found to be non-toxic against mammalian cells. In a mouse skin wound infection model, F6 was equipotent to the antibiotic fusidic acid in reducing MRSA burden.
各种报告表明，许多对所有可用的美国食品药品监督管理局批准的药物都具有耐药性的细菌需要开发新的化学支架作为抗生素。我们从化学文库中筛选出具有抗菌活性的化合物。最有效的化合物 F6-5 和 F6，以 1μg/ml 至 2μg/ml 的浓度抑制各种耐药革兰氏阳性细菌病原体的生长。这两种化合物对耐甲氧西林金黄色葡萄球菌（MRSA）、中间和耐万古霉素的金黄色葡萄球菌（VISA 和 VRSA 分别）和耐万古霉素的粪肠球菌（VRE）的临床分离株均有活性。耐药性产生实验表明，MRSA 可以对抗生素环丙沙星产生耐药性，但不能对 F6 产生耐药性。令人兴奋的是，F6 对哺乳动物细胞没有毒性。在小鼠皮肤创伤感染模型中，F6 在降低 MRSA 负担方面与抗生素夫西地酸等效。
