MexT Regulates the Type III Secretion System through MexS and PtrC in
            <i>Pseudomonas aeruginosa</i>

Jin, Yongxin; Yang, Hongjiang; Qiao, Mingqiang; Jin, Shouguang

doi:10.1128/jb.01079-10

Cited by 59 publications

(54 citation statements)

References 58 publications

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“…Mutants of the nfxC type have been isolated in the clinic, but they are not very common. The most likely explanation for this is their reduced virulence (102,109,111), together with the fact that these mutations appear to be less effective at engendering antibiotic resistance in vivo than they are under laboratory conditions (77).…”

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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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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“…In addition to MexEF-OprN, several MexT-regulated target genes in P. aeruginosa have been identified, highlighting the role of MexT as a global transcriptional regulator (66). Interestingly, not all MexTassociated phenotypes are dependent on MexEF-OprN, and other members of the MexT regulon have come into focus as potential players in pathogen-host interactions (9,19,66,67). The molecular mechanism by which MexT activates expression of its targets is thus an important physiological process in the context of understanding P. aeruginosa pathogenesis.…”

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confidence: 99%

MexT Functions as a Redox-Responsive Regulator Modulating Disulfide Stress Resistance in Pseudomonas aeruginosa

et al. 2012

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MexT is a global LysR transcriptional regulator known to modulate antibiotic resistance and virulence in Pseudomonas aeruginosa. In this study, a novel role for MexT in mediating intrinsic disulfide stress resistance was demonstrated, representing the first identified phenotype associated with inactivation of this regulator in wild-type cells. Disruption of mexT resulted in increased susceptibility to the disulfide stress elicitor diamide [diazenedicarboxylic acid bis(N,N,-di-methylamide)]. This compound is known to elicit a specific stress response via depletion of reduced glutathione and alteration of the cellular redox environment, implicating MexT in redox control. In support of this, MexT-regulated targets, including the MexEF-OprN multidrug efflux system, were induced by subinhibitory concentrations of diamide. A mexF insertion mutant also exhibited increased diamide susceptibility, implicating the MexEF-OprN efflux system in MexT-associated disulfide stress resistance. Purified MexT protein was observed to form an oligomeric complex in the presence of oxidized glutathione, with a calculated redox potential of ؊189 mV. This value far exceeds the thiol-disulfide redox potential of the bacterial cytoplasm, ensuring that MexT remains reduced under normal physiological conditions. MexT is activated by mutational disruption of the predicted quinone oxidoreductase encoded by mexS. Alterations in the cellular redox state were observed in a mexS mutant (PA14nfxC), supporting a model whereby the perception of MexS-associated redox signals by MexT leads to the induction of the MexEF-OprN efflux system, which, in turn, may mediate disulfide stress resistance via efflux of electrophilic compounds.

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“…Its derivative mutant that was selected by norfloxacin (referred to as a nfxC-type mutant) had a functional MexT protein and was characterized by attenuated pyocyanin production (5), high resistance to chloramphenicol (6), and absence of swarming motility (8) similar to the P1 strains in our study (3). mexT has been described as a mutational "hot spot," where mutations can contribute to global phenotypic changes in P. aeruginosa (6,(9)(10)(11). MexT is a transcriptional regulator of the MexEF-OprN efflux pump, which has been extensively characterized in the context of antimicrobial agents (12-15).…”

mentioning

confidence: 99%

Emergence of the P2 Phenotype in Pseudomonas aeruginosa PAO1 Strains Involves Various Mutations in mexT or mexF

Luong

Shogan

Zaborin

et al. 2013

Journal of Bacteriology

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We recently demonstrated that Pseudomonas aeruginosa PAO1 undergoes a pronounced phenotypic change when introduced into the intestines of rats during surgical injury. Recovered strains displayed a specific phenotype (termed the P2 phenotype) characterized by altered pyocyanin production, high collagenase activity, high swarming motility, low resistance to chloramphenicol, and increased killing of Caenorhabditis elegans compared to the inoculating strain (termed the P1 phenotype). The aims of this study were to characterize the differences between the P. aeruginosa P1 and P2 phenotypes in quorum sensing and competitiveness. We then determined the presence of the P2 phenotype among PAO1 strains from various laboratories. Results demonstrated that P2 cells display accelerated growth during early exponential phase and early activation of quorum-sensing systems and overcome the growth of P1 cells in a mixed population. Among eight PAO1 strains obtained from different laboratories, four exhibited the P2 phenotype. Of 27 mutants analyzed from the P. aeruginosa MPAO1 transposon library, 25 displayed P2 phenotypes. The P2 phenotype in both cases correlated with a lack of expression of mexE or mexF due to mutations in mexT and mexF genes. In summary, strains possessing the P2 phenotype are distributed among PAO1 strains commonly used across a variety of research laboratories. Genetically, they are characterized by various mutations in mexT or mexF. Stable genetic mutations that change phenotypes can arise as microbes adapt to their environment to maximize propagation. This ecologically dependent shift in phenotype has been documented in many bacterial species and in diverse contexts (1, 2). Recently, we demonstrated that the MPAO1 strain of Pseudomonas aeruginosa became transformed to (or selected for) a more virulent phenotype when present in the colon of rats subjected to preoperative radiation followed by colon resection and anastomosis (3). The strain recovered from the anastomotic tissue (termed MPAO1-P2, i.e., having the P2 phenotype) exhibited high collagenase activity, swarming ability, increased pyocyanin production in liquid medium, and increased tissue-destroying capacity compared to the initial strain (termed MPAO1-P1, having the P1 phenotype). Comparative genomic sequencing analysis revealed that MPAO1-P2 harbored a single-nucleotide polymorphism (SNP) in the mexT gene that results in a truncated and nonfunctional MexT protein. Transformation of mexT-P1 into MPAO1-P2 reverted the strain back to the P1 phenotype. The phenotypes of P. aeruginosa that are similar to P1 and P2 have been previously described (4-7). In the cited studies, the wild-type PAO1 strain harbored an 8-bp insertion in mexT that results in a nonfunctional MexT protein and a phenotype similar to P2. Its derivative mutant that was selected by norfloxacin (referred to as a nfxC-type mutant) had a functional MexT protein and was characterized by attenuated pyocyanin production (5), high resistance to chloramphenicol (6), and absence of swarming ...

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MexT Regulates the Type III Secretion System through MexS and PtrC in Pseudomonas aeruginosa

Cited by 59 publications

References 58 publications

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

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

MexT Functions as a Redox-Responsive Regulator Modulating Disulfide Stress Resistance in Pseudomonas aeruginosa

Emergence of the P2 Phenotype in Pseudomonas aeruginosa PAO1 Strains Involves Various Mutations in mexT or mexF

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