Institute for Molecular Bioscience, University of Queensland, Brisbane, Australia.
J Antimicrob Chemother. 2019 Mar 1;74(3):582-593. doi: 10.1093/jac/dky458.
Polymyxin 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.
We sought to compare and contrast the acquisition of resistance in an XDR Klebsiella pneumoniae (ST258) clinical isolate in vitro with all three lipopeptides to potentially unveil variations in their mode of action.
The 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.
Twenty 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, including crrB, mgrB, pmrB, phoPQ and yciM, along with novel mutations in qseC. Octapeptin C4-resistant isolates had mutations in mlaDF and pqiB, 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.
Octapeptin 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.
多黏菌素 B 和 E（黏菌素）在治疗 XDR 革兰氏阴性细菌感染方面发挥了关键作用；然而，耐药性已经出现。一种结构相关的脂肽，八肽素 C4，对 XDR 细菌表现出显著的效力，包括多黏菌素耐药株，但它的作用机制仍未定义。
我们试图比较和对比一株 XDR 肺炎克雷伯菌（ST258）临床分离株在体外对三种脂肽的耐药性获得情况，以潜在揭示它们作用机制的差异。
分离株在 20 天内暴露于递增浓度的多黏菌素和八肽素 C4 中。第 20 天的菌株进行 WGS、互补测定、药敏试验和脂质 A 分析。
20 天暴露于多黏菌素导致 MIC 增加了 1000 倍，而八肽素 C4 则增加了 4 倍。多黏菌素和八肽素耐药株之间没有交叉耐药性。多黏菌素耐药株的测序显示，在先前已知的耐药相关基因，包括 crrB、mgrB、pmrB、phoPQ 和 yciM 中，以及 qseC 中出现了新的突变。八肽素 C4 耐药株在 mlaDF 和 pqiB 中发生突变，这些基因与磷脂转运有关。这些遗传变异反映在脂质 A 的表型变化上。多黏菌素耐药株增加了脂质 A 磷酸盐基团上的 4-氨基-4-去氧阿拉伯糖修饰，而八肽素 C4 耐药株的脂质 A 中含有更高丰度的羟十四烷酸和棕榈酸。
八肽素 C4 的作用机制与多黏菌素不同，这突出了它作为未来治疗剂对抗日益严重的 XDR 细菌威胁的潜力。
