Genomic Research Laboratory, Service of Infectious Diseases, Geneva University Hospitals, Geneva, Switzerland
Genomic Research Laboratory, Service of Infectious Diseases, Geneva University Hospitals, Geneva, Switzerland.
Antimicrob Agents Chemother. 2018 Aug 27;62(9). doi: 10.1128/AAC.00788-18. Print 2018 Sep.
Multidrug-resistant infection has recently emerged as a worldwide clinical problem, and colistin is increasingly being used as a last-resort therapy. Despite its favorable bacterial killing, resistance and heteroresistance (HR) to colistin have been described. The purpose of the present study was to investigate the role of the PmrAB regulatory pathway in laboratory-selected mutants representative of global epidemic strains. From three unrelated clinical strains (sequence types 2, 3, and 20), eight colistin-resistant mutants were selected. Half of the mutants showed HR to colistin according to the reference method (population analysis profiling), whereas the other half exhibited stable resistance. M12I mutation within and M308R, S144KLAGS, and P170L mutations for were associated with HR to colistin, while T235I, A226T, and P233S mutations within were associated with stable resistance. The transcript levels of the operon were upregulated in all the mutants. Compensatory mutations were explored for some mutants. A single mutant (T235I mutant) displayed a compensatory mutation through IS mobilization within the gene that was associated with the loss of colistin resistance. The mutant resistance phenotype associated with T235I was partially restored in a -complementation assay turning to HR. The level of colistin resistance was correlated with the level of expression of in the -complemented strains. This report shows the role of different mutations in the PmrAB regulatory pathway and warns of the development of colistin HR that could be present but not easily detected through routine testing.
多药耐药感染最近已成为全球性临床问题，而多粘菌素正越来越多地被用作最后手段的治疗药物。尽管其具有良好的杀菌作用，但已描述了对多粘菌素的耐药性和异质性耐药（HR）。本研究的目的是研究 PmrAB 调节途径在代表全球流行株的实验室选择突变体中的作用。从三个无关的临床株（序列类型 2、3 和 20）中，选择了 8 个多粘菌素耐药突变体。一半的突变体根据参考方法（群体分析谱）显示对多粘菌素的 HR，而另一半则表现出稳定的耐药性。M12I 突变位于 内，M308R、S144KLAGS 和 P170L 突变位于 上，与多粘菌素的 HR 相关，而位于 内的 T235I、A226T 和 P233S 突变与稳定的耐药性相关。所有突变体的 操纵子转录水平均上调。对于一些突变体，探索了补偿性突变。单个突变体（T235I 突变体）通过 基因内的 IS 动员显示出补偿性突变，这与多粘菌素耐药性的丧失相关。T235I 突变体的耐药表型在 -互补测定中部分恢复，转化为 HR。多粘菌素耐药水平与 -互补菌株中 表达水平相关。本报告显示了 PmrAB 调节途径中不同突变的作用，并警告可能存在但通过常规检测不易检测到的多粘菌素 HR 发展。
