Comparative metabolomics revealed key pathways associated with the synergistic killing of multidrug-resistant Klebsiella pneumoniae by a bacteriophage-polymyxin combination.
Comparative metabolomics revealed key pathways associated with the synergistic killing of multidrug-resistant Klebsiella pneumoniae by a bacteriophage-polymyxin combination.
复制标题
比较代谢组学揭示了与通过噬菌体 - polymyxin组合通过协同杀死多药耐药性肺炎肺炎的关键途径。
DOI：
10.1016/j.csbj.2021.12.039
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发表时间：
2022
影响因子：
6
通讯作者：
Li J
中科院分区：
文献类型：
--
作者：
Han ML;Nang SC;Lin YW;Zhu Y;Yu HH;Wickremasinghe H;Barlow CK;Creek DJ;Crawford S;Rao G;Dai C;Barr JJ;Chan K;Turner Schooley R;Velkov T;Li J
在多重耐药的肺炎克雷伯菌中，出现了对最后一种多粘菌素的耐药性，噬菌体疗法是一种有前途的替代方案。然而，噬菌体单一疗法往往很快产生耐药性，很少有研究检验抗生素-噬菌体组合对肺炎克雷伯菌的抗药性。在这里，我们研究了多粘菌素B与新型噬菌体pK8的联合作用，以对抗携带mcr-1的多粘菌素耐药临床分离株KP II-503(多粘菌素B MIC，8 mg/L)。用多粘菌素B(16 mg/L)、噬菌体pK8(102pfu/mL)及其组合处理4h和24h，测定噬菌体基因组序列并分析细菌代谢产物。在24小时内，单用多粘菌素B的代谢变化很小；而在4小时和24小时，噬菌体-多粘菌素组合对柠檬酸循环、磷酸戊糖途径、氨基酸和核苷酸代谢都有显著的抑制作用，而单用噬菌体仅在4小时。在KP II-503中，对单独噬菌体的抗性与膜脂增加和氨基酸生物合成减少有关。值得注意的是，cAMP、cGMP和CCMP在噬菌体单独作用和联合作用仅在4h时显著增加(3.1-6.6log2倍)。这是首次研究多粘菌素-噬菌体联合增强杀菌作用的系统药理学研究，为肺炎克雷伯菌对噬菌体的杀灭、耐药性和抗生素-噬菌体联合作用提供了重要的机制信息。
Resistance to the last-line polymyxins is emerging in multidrug-resistant Klebsiella pneumoniae and phage therapy is a promising alternative. However, phage monotherapy often rapidly causes resistance and few studies have examined antibiotic-phage combinations against K. pneumoniae. Here, we investigated the combination of polymyxin B with a novel phage pK8 against an mcr-1-carrying polymyxin-resistant clinical isolate Kp II-503 (polymyxin B MIC, 8 mg/L). The phage genome was sequenced and bacterial metabolomes were analysed at 4 and 24 h following the treatment with polymyxin B (16 mg/L), phage pK8 (102 PFU/mL) and their combination. Minimal metabolic changes across 24 h were observed with polymyxin B alone; whereas a significant inhibition of the citrate cycle, pentose phosphate pathway, amino acid and nucleotide metabolism occurred with the phage-polymyxin combination at both 4 and 24 h, but with phage alone only at 4 h. The development of resistance to phage alone was associated with enhanced membrane lipid and decreased amino acid biosynthesis in Kp II-503. Notably, cAMP, cGMP and cCMP were significantly enriched (3.1–6.6 log2fold) by phage alone and the combination only at 4 h. This is the first systems pharmacology study to investigate the enhanced bacterial killing by polymyxin-phage combination and provides important mechanistic information on phage killing, resistance and antibiotic-phage combination in K. pneumoniae.
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影响因子：
6.4
作者：
Han, Mei-Ling;Zhu, Yan;Li, Jian
通讯作者：
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作者：
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