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作为抗生素和细菌成像载体的cystobactamid的合成研究产生了具有高体内功效的化合物
Synthetic studies of cystobactamids as antibiotics and bacterial imaging carriers lead to compounds with high in vivo efficacy

Chemical Science(中文翻译) ( IF 9.346 ) Pub Date : 2019-12-10 , DOI: 10.1039/c9sc04769g
GiambattistaTestolin, KatarinaCirnski, KatharinaRox, HansProchnow, VerenaFetz, CharlotteGrandclaudon, Tim AndreasMollner, AlainBaiyoumy, AntjeRitter, ChristianLeitner, JanaKrull, Joopvan den Heuvel, AurelieVassort, SylvieSordello, MostafaHamed, Walid A. M. A. M. Elgaher, JenniferHerrmann, RolfHartmann, RolfMüller, MarkBrönstrup

具有抗多药耐药革兰氏阴性细菌病原体生物活性的新型化学物质严重短缺。Cystobactamid是最近在粘细菌中发现的一种天然产物,是这种趋势的一个例外。它们具有不寻常化学结构,由低聚对氨基苯甲酸部分组成,通过抑制回旋酶而具有很高的抗菌活性。在该研究中,作者在五处定义了cystobactamid抗菌力的结构决定因素,这五处在三种不同的cystobactamid支架合成途径中有所不同。抗鲍曼不动杆菌效价可以提高十倍,达到0.06 μg/mL的MIC(最低抑菌浓度),与天然产物相比(MIC为0.5μg/ mL),以前鉴定的肺炎克雷伯菌的光谱差可以缩小。作者使用酰胺-三唑替代物防止了由抵抗因子AlbD引起的cystobactamid的蛋白水解降解。他们通过Cystobactamid的N末端四肽与氟硼二吡咯部分的缀合诱导了用于细菌成像的荧光团的选择性定位。最后,作者在大肠杆菌感染小鼠模型中实现了首次体内概念证明,其中衍生物22使肌肉、肺和肾脏中的细菌负荷(cfu,集落形成单位)减少了五个数量级。接受车辆治疗的小鼠。上述发现证明了cystobactamid是抗革兰氏阳性和革兰氏阴性细菌病原体感染的潜在先导结构。



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There is an alarming scarcity of novel chemical matter with bioactivity against multidrug-resistant Gram-negative bacterial pathogens. Cystobactamids, recently discovered natural products from myxobacteria, are an exception to this trend. Their unusual chemical structure, composed of oligomeric para-aminobenzoic acid moieties, is associated with a high antibiotic activity through the inhibition of gyrase. In this study, structural determinants of cystobactamid's antibacterial potency were defined at five positions, which were varied using three different synthetic routes to the cystobactamid scaffold. The potency against Acinetobacter baumannii could be increased ten-fold to an MIC (minimum inhibitory concentration) of 0.06 μg mL−1, and the previously identified spectrum gap of Klebsiella pneumoniae could be closed compared to the natural products (MIC of 0.5 μg mL−1). Proteolytic degradation of cystobactamids by the resistance factor AlbD was prevented by an amide-triazole replacement. Conjugation of cystobactamid's N-terminal tetrapeptide to a Bodipy moiety induced the selective localization of the fluorophore for bacterial imaging purposes. Finally, a first in vivo proof of concept was obtained in an E. coli infection mouse model, where derivative 22 led to the reduction of bacterial loads (cfu, colony-forming units) in muscle, lung and kidneys by five orders of magnitude compared to vehicle-treated mice. These findings qualify cystobactamids as highly promising lead structures against infections caused by Gram-positive and Gram-negative bacterial pathogens.
更新日期:2019-12-10

 

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