OBJECTIVES:Rifampicin, a potent first-line TB drug of the rifamycin group, shows only little activity against the emerging pathogen Mycobacterium abscessus. Reportedly, bacterial resistance to rifampicin is associated with polymorphisms in the target gene rpoB or the presence of enzymes that modify and thereby inactivate rifampicin. The aim of this study was to investigate the role of the MAB_0591 (arrMab)-encoded rifampicin ADP-ribosyltransferase (Arr_Mab) in innate high-level rifampicin resistance in M. abscessus. METHODS:Recombinant Escherichia coli and Mycobacterium tuberculosis strains expressing MAB_0591 were generated, as was an M. abscessus deletion mutant deficient for MAB_0591. MIC assays were used to study susceptibility to rifampicin and C25 carbamate-modified rifamycin derivatives. RESULTS:Heterologous expression of MAB_0591 conferred rifampicin resistance to E. coli and M. tuberculosis Rifamycin MIC values were consistently lower for the M. abscessus ΔarrMab mutant as compared with the M. abscessus ATCC 19977 parental type strain. The rifamycin WT phenotype was restored after complementation of the M. abscessus ΔarrMab mutant with arrMab Further MIC data demonstrated that a C25 modification increases rifamycin activity in WT M. abscessus However, MIC studies in the M. abscessus ΔarrMab mutant suggest that C25 modified rifamycins are still subject to modification by Arr_Mab CONCLUSIONS: Our findings identify Arr_Mab as the major innate rifamycin resistance determinant of M. abscessus. Our data also indicate that Arr_Mab-mediated rifamycin resistance in M. abscessus can only in part be overcome by C25 carbamate modification.

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目的:利福平是利福霉素组的一种有效的一线结核病药物,对新兴的病原性脓杆菌分枝杆菌几乎没有活性。据报道,细菌对利福平的抗性与靶基因rpoB中的多态性或修饰或使利福平失活的酶的存在有关。这项研究的目的是调查MAB_0591(arrMab)编码的利福平ADP-核糖基转移酶(Arr_Mab)在脓毒症先天性高水平利福平耐药中的作用。
方法:产生表达MAB_0591的重组大肠杆菌和结核分枝杆菌菌株,以及缺失MAB_0591的脓肿分支杆菌缺失突变体。 MIC分析用于研究对利福平和C25氨基甲酸酯修饰的利福霉素衍生物的敏感性。
结果:MAB_0591的异源表达赋予了利福平对大肠埃希菌和结核分枝杆菌的利福霉素耐药性。MIC值与脓毒症ΔarrMab突变体相比,在脓毒症中的ATCC 19977亲本型菌株均较低。脓肿分枝杆菌ΔarrMab突变体与arrMab互补后,利福霉素WT表型得以恢复。进一步的MIC数据表明,C25修饰增加了WT脓肿中利福霉素的活性。结论:我们的发现确定Arr_Mab是脓肿分支杆菌的主要先天利福霉素耐药性决定因素。我们的数据还表明,脓肿支原体中Arr_Mab介导的利福霉素耐药性只能通过C25氨基甲酸酯修饰来部分克服。

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