具有生物膜控制潜力的环丙沙星-氮氧化物杂化物。
Ciprofloxacin-nitroxide hybrids with potential for biofilm control.
作者信息
Verderosa Anthony D, de la Fuente-Núñez César, Mansour Sarah C, Cao Jicong, Lu Timothy K, Hancock Robert E W, Fairfull-Smith Kathryn E
机构信息
ARC Centre of Excellence for Free Radical Chemistry and Biotechnology, Faculty of Science and Engineering, Queensland University of Technology, Queensland 4001, Australia.
Synthetic Biology Group, MIT Synthetic Biology Center, Massachusetts Institute of Technology, Cambridge, MA, United States; Research Laboratory of Electronics, Massachusetts Institute of Technology, Cambridge, MA, United States; Department of Biological Engineering, Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, MA, United States; Broad Institute of MIT and Harvard, Cambridge, MA, United States; Harvard Biophysics Program, Harvard University, Boston, MA, United States; The Center for Microbiome Informatics and Therapeutics, Cambridge, MA, United States.
出版信息
Eur J Med Chem. 2017 Sep 29;138:590-601. doi: 10.1016/j.ejmech.2017.06.058. Epub 2017 Jun 28.
As bacterial biofilms display extreme tolerance to conventional antibiotic treatments, it has become imperative to develop new antibacterial strategies with alternative mechanisms of action. Herein, we report the synthesis of a series of ciprofloxacin-nitroxide conjugates and their corresponding methoxyamine derivatives in high yield. This was achieved by linking various nitroxides or methoxyamines to the secondary amine of the piperazine ring of ciprofloxacin using amide bond coupling. Biological evaluation of the prepared compounds on preformed P. aeruginosa biofilms in flow cells revealed substantial dispersal with ciprofloxacin-nitroxide hybrid 25, and virtually complete killing and removal (94%) of established biofilms in the presence of ciprofloxacin-nitroxide hybrid 27. Compounds 25-28 were shown to be non-toxic in both human embryonic kidney 293 (HEK 293) cells and human muscle rhabdomyosarcoma (RD) cells at concentrations up to 40 μM. Significantly, these hybrids demonstrate the potential of antimicrobial-nitroxide agents to overcome the resistance of biofilms to antimicrobials via stimulation of biofilm dispersal or through direct cell killing.
由于细菌生物膜对传统抗生素治疗表现出极强的耐受性，开发具有替代作用机制的新型抗菌策略已变得势在必行。在此，我们报告了一系列环丙沙星 - 氮氧化物缀合物及其相应甲氧基胺衍生物的高产率合成。这是通过使用酰胺键偶联将各种氮氧化物或甲氧基胺连接到环丙沙星哌嗪环的仲胺上来实现的。对制备的化合物在流动池中预先形成的铜绿假单胞菌生物膜上进行生物学评估，结果显示环丙沙星 - 氮氧化物杂化物25能使生物膜大量分散，在环丙沙星 - 氮氧化物杂化物27存在的情况下，已形成的生物膜几乎能被完全杀灭和清除（94%）。化合物25 - 28在浓度高达40μM时，对人胚肾293（HEK 293）细胞和人肌肉横纹肌肉瘤（RD）细胞均无毒。值得注意的是，这些杂化物证明了抗菌 - 氮氧化物制剂通过刺激生物膜分散或直接杀灭细胞来克服生物膜对抗菌剂耐药性的潜力。
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