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Isopedopeptins A–H: Cationic Cyclic Lipodepsipeptides from Pedobacter cryoconitis UP508 Targeting WHO Top-Priority Carbapenem-Resistant Bacteria
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2020-10-14 , DOI: 10.1021/acschembio.0c00568
Christina Nord 1 , Joakim Bjerketorp 1, 2 , Jolanta J. Levenfors 1, 2 , Sha Cao 3 , Adam A. Strömstedt 4 , Bengt Guss 5 , Rolf Larsson 6 , Diarmaid Hughes 3 , Bo Öberg 2, 4 , Anders Broberg 1
Affiliation  

Pedobacter cryoconitis strain UP508 was isolated from a soil sample using a mixture of ampicillin, kanamycin, and nalidixic acid for selection. UP508 was found to produce >30 unknown antibacterial peptides, of which eight, isopedopeptins A–H (18), were isolated by bioassay-guided fractionation and characterized with respect to structures and biological properties. Compounds 18 were all composed of nine amino acid residues and one 3-hydroxy fatty acid residue, and the structures were ring-closed via an ester bond from the C-terminal aspartic acid to the 3-hydroxy fatty acid. The differences between the peptides were the size and branching of the 3-hydroxy fatty acid and the presence of a valine or a 3-hydroxyvaline residue. The isopedopeptins mainly had activity against Gram-negative bacteria, and isopedopeptin B (2), which had the best combination of antibacterial activity, in vitro cytotoxicity, and hemolytic properties, was selected for further studies against a larger panel of Gram-negative bacteria. Isopedopeptin B was found to have good activity against strains of WHO top-priority Gram-negative bacteria, i.e., carbapenem-resistant Acinetobacter baumannii, Escherichia coli, and Pseudomonas aeruginosa, with minimal inhibitory concentrations (MIC) down to 1, 2, and 4 μg/mL, respectively. Furthermore, compound 2 had activity against colistin-resistant strains of A. baumannii, E. coli, and Klebsiella pneumoniae, with a MIC down to 8, 2, and 4 μg/mL, respectively. Compound 6 was tested in an E. coli liposome system where it induced significant leakage, indicating membrane disruption as one mechanism involved in isopedopeptin antibacterial activity. Isopedopeptin B stands out as a promising candidate for further studies with the goal to develop a new antibiotic drug.

中文翻译:

Isopedopeptins A–H:致死性肺炎双歧杆菌UP508的阳离子环脂肽针对WHO最优先耐碳青霉烯的细菌

使用氨苄青霉素,卡那霉素和萘啶酸的混合物从土壤样品中分离出古细菌Peconbacter低温圆锥炎菌株UP508。UP508被发现产生> 30个未知抗菌肽,其中8,isopedopeptins A-H(1 - 8)中,通过生物测定引导的分级分离分离并表征相对于结构和生物学性质。化合物18它们均由9个氨基酸残基和1个3-羟基脂肪酸残基组成,并且该结构通过从C-末端天冬氨酸到3-羟基脂肪酸的酯键闭环。肽之间的差异是3-羟基脂肪酸的大小和分支以及缬氨酸或3-羟基缬氨酸残基的存在。异肽肽主要对革兰阴性菌具有活性,异肽肽B(2)具有抗菌活性,体外细胞毒性和溶血性的最佳结合,被选为对较大革兰阴性菌的进一步研究。已发现异肽素B对WHO最重要的革兰氏阴性细菌菌株具有良好的活性,即耐碳青霉烯鲍曼不动杆菌大肠杆菌铜绿假单胞菌的最小抑菌浓度(MIC)分别低至1、2和4μg/ mL。此外,化合物2鲍曼不动杆菌大肠杆菌肺炎克雷伯菌的大肠菌素抗性菌株具有活性,MIC分别降至8、2和4μg/ mL。在大肠杆菌中测试了化合物6脂质体系统在其中引起明显的渗漏,表明膜破坏是参与异七肽抗菌活性的一种机制。以开发一种新的抗生素为目标,异肽素B可以作为进一步研究的有希望的候选者。
更新日期:2020-11-21
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