Isopedopeptins A–H: Cationic Cyclic Lipodepsipeptides from Pedobacter cryoconitis UP508 Targeting WHO Top-Priority Carbapenem-Resistant Bacteria,ACS Chemical Biology

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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 (1–8), were isolated by bioassay-guided fractionation and characterized with respect to structures and biological properties. Compounds 1–8 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1 – 8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，大肠杆菌和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对鲍曼不动杆菌，大肠杆菌和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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