Octapeptin C4 and polymyxin resistance occur via distinct pathways in an epidemic XDR Klebsiella pneumoniae ST258 isolate.
Octapeptin C4 and polymyxin resistance occur via distinct pathways in an epidemic XDR Klebsiella pneumoniae ST258 isolate.
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在流行性 XDR 肺炎克雷伯菌 ST258 分离株中，八肽素 C4 和多粘菌素耐药性通过不同的途径发生。
DOI：
10.1093/jac/dky458
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Cooper,MatthewA
中科院分区：
文献类型：
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作者：
Pitt,MirandaE;Cao,MinhDuc;Butler,MarkS;Ramu,Soumya;Ganesamoorthy,Devika;Blaskovich,MarkAT;Coin,LachlanJM;Cooper,MatthewA
背景多粘菌素 B 和 E（多粘菌素）在 XDR 革兰氏阴性细菌感染的治疗中发挥着关键作用；然而，阻力已经出现。结构相关的脂肽八肽 C4 对 XDR 细菌（包括多粘菌素耐药菌株）显示出显着的效力，但其作用方式仍不清楚。 目的我们试图将 XDRK 肺炎雷伯菌 (ST258) 临床分离株体外耐药性的获得与所有三种脂肽进行比较和对比，以潜在地揭示变异 方法将分离株暴露于浓度不断增加的多粘菌素和八肽C4 20天内。第 20 天的菌株进行全基因组测序、互补分析、抗菌药物敏感性测试和脂质 A 分析。结果暴露于多粘菌素 20 天导致 MIC 增加 1000 倍，而八肽 C4 则增加 4 倍。多粘菌素和八肽素抗性菌株之间没有观察到交叉抗性。对多粘菌素耐药菌株的测序揭示了先前已知的耐药相关基因的突变，包括 crrB、mgrB、pmrB、phoPQ 和 dyciM，以及 qseC 中的新突变。八肽素 C4 抗性分离株在与磷脂转运相关的基因 mlaDF 和 pqiB 中存在突变。这些遗传变异反映在脂质 A 的明显表型变化中。多粘菌素抗性分离株增加了脂质 A 磷酸基团的 4-氨基-4-脱氧阿拉伯糖强化，而八肽素 C4 抗性菌株的脂质 A 含有更高丰度的羟基肉豆蔻酸盐和棕榈酰酸盐。结论八肽素 C4 具有 与多粘菌素相比，其作用模式不同，凸显了其作为未来治疗剂对抗 XDR 细菌日益增长的威胁的潜力。
BackgroundPolymyxin B and E (colistin) have been pivotal in the treatment of XDR Gram-negative bacterial infections; however, resistance has emerged. A structurally related lipopeptide, octapeptin C4, has shown significant potency against XDR bacteria, including polymyxin-resistant strains, but its mode of action remains undefined.ObjectivesWe sought to compare and contrast the acquisition of resistance in an XDRKlebsiella pneumoniae(ST258) clinical isolatein vitrowith all three lipopeptides to potentially unveil variations in their mode of action.MethodsThe isolate was exposed to increasing concentrations of polymyxins and octapeptin C4 over 20 days. Day 20 strains underwent WGS, complementation assays, antimicrobial susceptibility testing and lipid A analysis.ResultsTwenty days of exposure to the polymyxins resulted in a 1000-fold increase in the MIC, whereas for octapeptin C4 a 4-fold increase was observed. There was no cross-resistance observed between the polymyxin- and octapeptin-resistant strains. Sequencing of polymyxin-resistant isolates revealed mutations in previously known resistance-associated genes, includingcrrB,mgrB,pmrB,phoPQandyciM, along with novel mutations inqseC. Octapeptin C4-resistant isolates had mutations inmlaDFandpqiB, genes related to phospholipid transport. These genetic variations were reflected in distinct phenotypic changes to lipid A. Polymyxin-resistant isolates increased 4-amino-4-deoxyarabinose fortification of lipid A phosphate groups, whereas the lipid A of octapeptin C4-resistant strains harboured a higher abundance of hydroxymyristate and palmitoylate.ConclusionsOctapeptin C4 has a distinct mode of action compared with the polymyxins, highlighting its potential as a future therapeutic agent to combat the increasing threat of XDR bacteria.