Antibiotic inducibility of the mexXY multidrug efflux operon of Pseudomonas aeruginosa: involvement of the MexZ anti-repressor ArmZ.
Antibiotic inducibility of the mexXY multidrug efflux operon of Pseudomonas aeruginosa: involvement of the MexZ anti-repressor ArmZ.
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DOI：
10.1371/journal.pone.0056858
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Poole K
中科院分区：
文献类型：
--
作者：
Hay T;Fraud S;Lau CH;Gilmour C;Poole K
在野生型铜绿假单胞菌中，Mexxy多药外排操纵子的表达被核糖体靶向抗菌剂壮观霉素显著增强(18倍)，这完全依赖于PA5471基因的产物。在缺乏编码Mexxy基因表达抑制因子的mexZ基因的突变菌株中，外排操纵子的表达略有增加(5倍)，但对壮观霉素仍有反应(18倍)。然而，大观霉素诱导MexZ突变体中的Mexxy表达是独立于PA5471的，这表明PA5471作为一个抗阻遏子(被称为ARMZ，即抗抑制子MexZ)只起到调节MexZ的阻遏活性的作用，额外的基因(S)/基因产物(S)提供了大部分抗菌剂诱导的Mexxy表达。通过细菌双杂交实验证实了MexZ和ARMZ之间的相互作用，这与PA5471/ARMZ作为MexZ抗抑制因子的作用一致。影响这种相互作用的突变(P68S、G76S、R216C、R221W、R221Q、G231D和G252S)被发现并定位于一个ARMZ结构模型的一个区域，该区域可能代表MexZ相互作用结构域。将代表性突变引入到铜绿假单胞菌的染色体中，减少(P68S，G76S)或消除(R216C，R2211W)抗菌剂诱导Mexxy基因的表达，使突变株对泛氨基糖苷类药物敏感。这些数据证实了ARMZ-MexZ相互作用对铜绿假单胞菌中抗菌素诱导的Mexxy表达和内在氨基糖苷类耐药性的重要性。
Expression of the mexXY multidrug efflux operon in wild type Pseudomonas aeruginosa is substantially enhanced by the ribosome-targeting antimicrobial spectinomycin (18-fold) and this is wholly dependent upon the product of the PA5471 gene. In a mutant strain lacking the mexZ gene encoding a repressor of mexXY gene expression, expression of the efflux operon increases modestly (5-fold) and is still responsive (18-fold) to spectinomycin. Spectinomycin induction of mexXY expression in the mexZ mutant is, however, independent of PA5471 suggesting that PA5471 functions as an anti-repressor (dubbed ArmZ for anti-repressor MexZ) that serves only to modulate MexZ's repressor activity, with additional gene(s)/gene product(s) providing for the bulk of the antimicrobial-inducible mexXY expression. Consistent with PA5471/ArmZ functioning as a MexZ anti-repressor, an interaction between MexZ and ArmZ was confirmed using a bacterial 2-hybrid assay. Mutations compromising this interaction (P68S, G76S, R216C, R221W, R221Q, G231D and G252S) were identified and localized to one region of an ArmZ structural model that may represent a MexZ-interacting domain. Introduction of representative mutations into the chromosome of P. aeruginosa reduced (P68S, G76S) or obviated (R216C, R2211W) antimicrobial induction of mexXY gene expression, rendering the mutants pan-aminoglycoside-susceptible. These data confirm the importance of an ArmZ-MexZ interaction for antimicrobial-inducible mexXY expression and intrinsic aminoglycoside resistance in P. aeruginosa.
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