Structure, Function, and Biosynthetic Origin of Octapeptin Antibiotics Active against Extensively Drug-Resistant Gram-Negative Bacteria.
Structure, Function, and Biosynthetic Origin of Octapeptin Antibiotics Active against Extensively Drug-Resistant Gram-Negative Bacteria.
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DOI：
10.1016/j.chembiol.2018.01.005
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发表时间：
2018-04-19
影响因子：
8.6
通讯作者：
Cooper MA
中科院分区：
文献类型：
--
作者：
Velkov T;Gallardo-Godoy A;Swarbrick JD;Blaskovich MAT;Elliott AG;Han M;Thompson PE;Roberts KD;Huang JX;Becker B;Butler MS;Lash LH;Henriques ST;Nation RL;Sivanesan S;Sani MA;Separovic F;Mertens H;Bulach D;Seemann T;Owen J;Li J;Cooper MA
对最后一种抗生素粘菌素的耐药性现在很普遍，迫切需要新的治疗方法。我们报告的第一个在toto化学合成和临床前评价octapeptin，一类脂肽结构相关的粘菌素。octapeptin生物合成簇由三种非核糖体肽合成酶（OctA、OctB、OctC）组成，其产生两亲性抗生素octapeptin C4，其显示结合至膜并使膜脱附。虽然在体外对MDR菌株有活性，但八肽肽素C4显示出较差的体内功效，最可能是由于高血浆蛋白结合。NMR溶液结构，经验结构-活性和结构-毒性模型被用来设计合成的八肽活性对MDR和广泛耐药（XDR）细菌。然后对支架进行微妙的改变，以减少血浆蛋白结合，同时保持对MDR和XDR细菌的活性。在具有粘菌素耐药性铜绿假单胞菌临床分离株的鼠菌血症模型中证明了体内疗效。
Resistance to the last-resort antibiotic colistin is now widespread and new therapeutics are urgently required. We report the first in toto chemical synthesis and pre-clinical evaluation of octapeptins, a class of lipopeptides structurally related to colistin. The octapeptin biosynthetic cluster consisted of three non-ribosomal peptide synthetases (OctA, OctB, OctC) that produced an amphiphilic antibiotic, octapeptin C4, which was shown to bind to and depolarize membranes. Whilst active against MDR strains in vitro, octapeptin C4 displayed poor in vivo efficacy, most likely due to high plasma protein binding. NMR solution structures, empirical structure-activity and structure-toxicity models were used to design synthetic octapeptins active against MDR and extensively-drug resistance (XDR) bacteria. The scaffold was then subtly altered to reduce plasma protein binding, while maintaining activity against MDR and XDR bacteria. In vivo efficacy was demonstrated in a murine bacteremia model with a colistin-resistant P. aeruginosa clinical isolate.
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影响因子：
4.9
作者：
Li, J;Milne, RW;Coulthard, K
通讯作者：
Coulthard, K
影响因子：
3.3
作者：
PARKER, WL;RATHNUM, ML
通讯作者：
RATHNUM, ML
影响因子：
4.8
作者：
Huang, Yen-Hua;Colgrave, Michelle L.;Craik, David J.
通讯作者：
Craik, David J.
影响因子：
2.9
作者：
Henriques, Sonia Troeira;Pattenden, Leonard Keith;Castanho, Miguel A. R. B.
通讯作者：
Castanho, Miguel A. R. B.
DOI：
10.1111/j.1749-6632.1974.tb43286.x
发表时间：
1974-01-01
影响因子：
5.2
作者：
MEYERS, E;PARKER, WL;STROMING.JL
通讯作者：
STROMING.JL