Polymyxin Resistance in Acinetobacter baumannii: Genetic Mutations and Transcriptomic Changes in Response to Clinically Relevant Dosage Regimens.
Polymyxin Resistance in Acinetobacter baumannii: Genetic Mutations and Transcriptomic Changes in Response to Clinically Relevant Dosage Regimens.
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DOI：
10.1038/srep26233
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发表时间：
2016-05-19
影响因子：
4.6
通讯作者：
Li J
中科院分区：
文献类型：
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作者：
Cheah SE;Johnson MD;Zhu Y;Tsuji BT;Forrest A;Bulitta JB;Boyce JD;Nation RL;Li J
多粘菌素通常是用于治疗多重耐药鲍曼不动杆菌引起的感染的最后一线治疗药物。最近有关多粘菌素耐药鲍曼不动杆菌的报道凸显了研究多粘菌素耐药机制的迫切需要。本研究采用基因组和转录组分析来研究鲍曼不动杆菌 AB307-0294 的多粘菌素耐药机制，使用体外动态模型模拟多粘菌素 B 和粘菌素的四种不同临床相关剂量方案超过 96 小时。在 1 小时内达到峰值浓度高于 1mg/L 的多粘菌素 B 剂量方案可显着杀死细菌（约 5 log10CFU/mL），而粘菌素的逐渐积累导致没有细菌杀死。在所有剂量方案中均观察到多粘菌素耐药性；在无药传代过程中，8 个细菌样品中有 6 个样品观察到部分敏感性恢复。稳定的多粘菌素抗性样本含有 pmrB 突变。稳定和不稳定多粘菌素抗性样品的转录组没有显着差异，并且具有与外膜结构和生物发生相关的基因表达改变的特征。这些发现通过对先前发表的 ATCC19606 菌株转录组学数据的综合分析得到了进一步支持。我们的结果为了解多粘菌素暴露后多粘菌素耐药机制以及探索有效联合疗法的必要性奠定了基础。
Polymyxins are often last-line therapeutic agents used to treat infections caused by multidrug-resistant A. baumannii. Recent reports of polymyxin-resistant A. baumannii highlight the urgent need for research into mechanisms of polymyxin resistance. This study employed genomic and transcriptomic analyses to investigate the mechanisms of polymyxin resistance in A. baumannii AB307-0294 using an in vitro dynamic model to mimic four different clinically relevant dosage regimens of polymyxin B and colistin over 96 h. Polymyxin B dosage regimens that achieved peak concentrations above 1 mg/L within 1 h caused significant bacterial killing (~5 log10CFU/mL), while the gradual accumulation of colistin resulted in no bacterial killing. Polymyxin resistance was observed across all dosage regimens; partial reversion to susceptibility was observed in 6 of 8 bacterial samples during drug-free passaging. Stable polymyxin-resistant samples contained a mutation in pmrB. The transcriptomes of stable and non-stable polymyxin-resistant samples were not substantially different and featured altered expression of genes associated with outer membrane structure and biogenesis. These findings were further supported via integrated analysis of previously published transcriptomics data from strain ATCC19606. Our results provide a foundation for understanding the mechanisms of polymyxin resistance following exposure to polymyxins and the need to explore effective combination therapies.