MexZ-mediated regulation of multidrug efflux pump expression in by binding on the intergenic DNA

Matsuo, Yasuhiro; Eda, Shima; Gotoh, Nobuyuki; Yoshihara, Eisaku; Nakae, Taiji

doi:10.1016/j.femsle.2004.07.010

Cited by 71 publications

(65 citation statements)

References 28 publications

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“…The above results did not rule out the possibility that some drugs might interact directly with MexZ and modulate its repressor activity, reminiscent of tetracycline induction of the tetA(B) efflux determinant following its interaction with and modulation of the activity of the TetR repressor of tetA(B) gene expression (6). Still, a recent study showing that drugs known to induce mexXY expression neither bind to MexZ nor have any impact on MexZ binding to the mexXY promoter region (14) precludes this possibility. To assess the possible significance of antibiotic-ribosome interaction with respect to antibiotic induction of mexXY expression, then, the impact of known ribosomal protection mechanisms (tetO, tetracycline resistance; ermBP, erythromycin resistance) on antibiotic-inducible mexXY expression was examined in the P. aeruginosa ⌬mexAB-oprM mutant K1119.…”

Section: Resultsmentioning

confidence: 82%

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Induction of the MexXY Efflux Pump in Pseudomonas aeruginosa Is Dependent on Drug-Ribosome Interaction

Jeannot¹,

Sobel

Garch³

et al. 2005

J Bacteriol

138

145

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MexXY is an inducible efflux system that contributes to the natural resistance of Pseudomonas aeruginosa to antibiotics. Experiments involving real-time PCR after reverse transcription in reference strain PAO1 showed concentration-dependent induction of gene mexY by various ribosome inhibitors (e.g., chloramphenicol, tetracycline, macrolides, and aminoglycosides) but not by antibiotics acting on other cellular targets (e.g., ␤-lactams, fluoroquinolones). Confirming a functional link between the efflux system and the translational machinery, ribosome protection by plasmid-encoded proteins TetO and ErmBP increased the resistance of a ⌬mexAB-oprM mutant of PAO1 to tetracycline and erythromycin, respectively, as well as the concentrations of both drugs required to induce mexY. Furthermore, spontaneous mutations resulting in specific resistance to dihydrostreptomycin or spectinomycin also raised the minimal drug concentration for mexXY induction in strain PAO1. While strongly upregulated in a PAO1 mutant defective in gene mexZ (which codes for a putative repressor of operon mexXY), gene mexY remained inducible by agents such as tetracycline, chloramphenicol, and spectinomycin, suggesting additional regulatory loci for mexXY. Altogether, these data demonstrate physiological interplays between MexXY and the ribosome and are suggestive of an alternative function for MexXY beyond antibiotic efflux.

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Section: Resultsmentioning

confidence: 82%

“…This strongly suggests that like mexAB-oprM (3,21), mexXY is under the control of several regulatory loci. Recently, the mexZ-encoded product, a probable TetR family repressor, has been shown to bind as a dimer to the mexZ-mexXY intergenic region encompassing two putative overlapping promoters set in opposite orientations (14).…”

mentioning

confidence: 99%

Induction of the MexXY Efflux Pump in Pseudomonas aeruginosa Is Dependent on Drug-Ribosome Interaction

Jeannot¹,

Sobel

Garch³

et al. 2005

J Bacteriol

138

145

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“…In spite of these clear disadvantages, nfxB mutants are readily selected following exposure to fluoroquinolones, azithromycin, and even biocides like triclosan both in vitro and during clinical therapy (37,100,168). Another regulator is MexZ, which belongs to the TetR family and normally represses the transcription of the mexXY genes by binding to the mexZmexX intergenic region (157,264). Mutations in MexZ have been found to participate in the acquisition of moderate aminoglycoside resistance in CF isolates of P. aeruginosa (256) and may be a significant cause of impermeability-type aminoglycoside resistance, which occurs in 10% or more of patients treated extensively with aminoglycosides.…”

Section: Mutational Resistance Related To Efflux Pumpsmentioning

confidence: 99%

Adaptive and Mutational Resistance: Role of Porins and Efflux Pumps in Drug Resistance

2012

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SUMMARY The substantial use of antibiotics in the clinic, combined with a dearth of new antibiotic classes, has led to a gradual increase in the resistance of bacterial pathogens to these compounds. Among the various mechanisms by which bacteria endure the action of antibiotics, those affecting influx and efflux are of particular importance, as they limit the interaction of the drug with its intracellular targets and, consequently, its deleterious effects on the cell. This review evaluates the impact of porins and efflux pumps on two major types of resistance, namely, mutational and adaptive types of resistance, both of which are regarded as key phenomena in the global rise of antibiotic resistance among pathogenic microorganisms. In particular, we explain how adaptive and mutational events can dramatically influence the outcome of antibiotic therapy by altering the mechanisms of influx and efflux of antibiotics. The identification of porins and pumps as major resistance markers has opened new possibilities for the development of novel therapeutic strategies directed specifically against these mechanisms.

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“…While this is consistent with efflux of these agents being the intended function of the MexXY-OprM system, it is interesting that not all antibiotic substrates, but only those agents known to target the ribosome, induce mexXY expression (23). Moreover, in contrast to other drug-inducible multidrug efflux systems (e.g., QacA, an MF family exporter in Staphylococcus aureus), where drug binding to the cognate regulator (i.e., QacR) alleviates repression of the efflux gene (i.e., qacA) (16), providing some support for these systems as intended determinants of drug efflux, MexXY antimicrobial substrates that induce mexXY expression do not interact with or directly modulate the activity of the mexXY repressor, MexZ (32). Also, the observation that ribosome protection mechanisms compromise drug-inducible mexXY expression (23) supports this efflux system being recruited in response to ribosome disruption and not to antibiotics per se.…”

mentioning

confidence: 99%

Antibiotic Inducibility of the MexXY Multidrug Efflux System of Pseudomonas aeruginosa : Involvement of the Antibiotic-Inducible PA5471 Gene Product

2006

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The MexXY components of the MexXY-OprM multidrug efflux system of Pseudomonas aeruginosa are encoded by a MexZ repressor-regulated operon that is inducible by antibiotics that target the ribosome. Mutant strains disrupted in a gene, PA5471, were shown to be compromised for drug-inducible mexXY expression and, therefore, MexXY-OprM-mediated antimicrobial resistance. The PA5471 gene was inducible by the same ribosometargeting agents that induce mexXY expression. Moreover, vector-driven expression of cloned PA5471 was sufficient to promote mexXY expression and MexXY-mediated resistance in the absence of antibiotic exposure, consistent with PA5471 directly or indirectly activating mexXY expression following its own upregulation in response to antibiotics. The requirement for PA5471 for mexXY expression and antimicrobial resistance was, however, obviated in mutants lacking the MexZ repressor of mexXY expression, suggesting that PA5471 directly or indirectly modulates MexZ activity in effecting mexXY expression. While the recruitment of PA5471 and MexXY in response to ribosome disruption by antimicrobials is consistent with their genes playing a role in protecting cells from the adverse consequences of disrupting the translation process, reminiscent of transtranslation, these genes appear to operate independently in their contribution to resistance: mutants defective in trans-translation showed a much more modest (twofold) decrease in resistance to ribosome-targeting agents than those lacking PA5471 or MexXY, and this decrease was observed whether functional PA5471/MexXY was present or not.Multidrug efflux systems of the resistance-nodulation-division (RND) family contribute significantly to intrinsic and acquired resistance to antimicrobials in a number of gram-negative bacteria (43, 45). Despite their significance as determinants of antibiotic resistance, however, RND-type multidrug exporters also, in many instances, accommodate biocides (42, 45), organic solvents (48), detergents (43), including bile salts (9,18,46,60), toxic fatty acids/lipids (54), and in some instances, plant-derived antimicrobials (phytoalexins and isoflavonoids) (7, 39), metabolic inhibitors (52), organometallic compounds (tributyltin) (25), quorum-sensing effector molecules (13,26,40), and, possibly, virulence factors (21) in addition to antibiotics. Clearly, RND pumps can and do function as other than antibiotic exporters.Pseudomonas aeruginosa expresses several three-component RND-type multidrug efflux systems, among which four, MexAB-

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MexZ-mediated regulation of multidrug efflux pump expression in by binding on the intergenic DNA

Cited by 71 publications

References 28 publications

Induction of the MexXY Efflux Pump in Pseudomonas aeruginosa Is Dependent on Drug-Ribosome Interaction

Induction of the MexXY Efflux Pump in Pseudomonas aeruginosa Is Dependent on Drug-Ribosome Interaction

Adaptive and Mutational Resistance: Role of Porins and Efflux Pumps in Drug Resistance

Antibiotic Inducibility of the MexXY Multidrug Efflux System of Pseudomonas aeruginosa : Involvement of the Antibiotic-Inducible PA5471 Gene Product

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