Cloning and nucleotide sequence of the Pseudomonas aeruginosa nfxB gene, conferring resistance to new quinolones

Okazaki, Takashi; Hirai, Keiji

doi:10.1016/0378-1097(92)90386-3

Cited by 29 publications

(42 citation statements)

References 14 publications

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“…NfxB in P. aeruginosa, the closest homologue of PqrA, negatively regulates its own gene as well as the mexC-mexDoprJ operon (32). Two known nfxB mutations (H87R and R42G) that fail to repress target genes and cause multiple antibiotic resistance are recessive to the wild-type allele (30,32). Although the in vitro binding results are not available, both mutations are thought to reduce the DNA-binding activity of NfxB.…”

Section: Discussionmentioning

confidence: 99%

ThepqrABOperon Is Responsible for Paraquat Resistance inStreptomyces coelicolor

et al. 2003

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Paraquat (methyl viologen)-resistant mutants of Streptomyces coelicolor A3(2) that grew and sporulated normally in the presence of paraquat were isolated. Based on the positions of the mutant loci in the genetic map, we isolated the pqr (paraquat resistance) gene whose mutation (pqr501) caused a dominant paraquatresistant phenotype. The pqr locus consists of two genes (pqrA and pqrB) that form a transcription unit. The pqrA gene encodes a protein with a TetR-like DNA-binding motif, and the pqrB gene encodes a putative efflux pump of the major facilitator superfamily. The pqr501 mutation was a base substitution changing arginine-18 to glutamine (R18Q) near the helix-turn-helix motif in PqrA. A pqrA null mutant exhibited similar paraquat resistance, and an increase in the amount of pqrA promoter-driven transcripts of about eightfold was observed for the pqrA501 mutant. These results suggest that PqrA is a negative regulator of its own operon. Deletion of the pqrAB operon caused cells to be very sensitive to paraquat, consistent with the prediction that PqrB may function as a paraquat-efflux pump. Purified PqrA protein specifically bound to the pqrA promoter region, whereas mutant R18Q protein did not, indicating that PqrA is a direct autoregulator of its own operon.

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Section: Discussionmentioning

confidence: 99%

ThepqrABOperon Is Responsible for Paraquat Resistance inStreptomyces coelicolor

et al. 2003

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“…Mutations in nalB have been found quite often in resistant clinical isolates, in particular in those from patients who had been treated with ␤-lactams (134,272). The efflux pump MexCD-OprJ is similarly regulated by the product of the nfxB gene, which is adjacent to but in an opposite orientation from the operon encoding the pump components (188). nfxB mutants were first isolated due to their norfloxacinresistant phenotype and also displayed hypersusceptibility to ␤-lactams and aminoglycosides (92).…”

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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“…A second efflux system, MexCD-OprJ (41), is responsible for efflux of quinolones, erythromycin (29), and cephalosporins (12,27). Its expression is totally repressed by the transcriptional regulator NfxB (35,49). The third efflux pump, MexEFOprN, transports chloramphenicol as well as quinolones, is overexpressed in nfxC type mutants (18), and is positively regulated by the transcriptional activator MexT (16).…”

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confidence: 99%

Overexpression of the MexEF-OprN Multidrug Efflux System Affects Cell-to-Cell Signaling in Pseudomonas aeruginosa

Köhler¹,

Delden²,

Curty³

et al. 2001

J Bacteriol

258

265

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Intrinsic and acquired antibiotic resistance of the nosocomial pathogen Pseudomonas aeruginosa is mediated mainly by the expression of several efflux pumps of broad substrate specificity. Here we report that nfxC type mutants, overexpressing the MexEF-OprN efflux system, produce lower levels of extracellular virulence factors than the susceptible wild type. These include pyocyanin, elastase, and rhamnolipids, three factors controlled by the las and rhl quorum-sensing systems of P. aeruginosa. In agreement with these observations are the decreased transcription of the elastase gene lasB and the rhamnosyltransferase genes rhlAB measured in nfxC type mutants. Expression of the lasR and rhlR regulator genes was not affected in the nfxC type mutant. In contrast, transcription of the C4-homoserine lactone (C4-HSL) autoinducer synthase gene rhlI was reduced by 50% in the nfxC type mutant relative to that in the wild type. This correlates with a similar decrease in C4-HSL levels detected in supernatants of the nfxC type mutant. Transcription of an rhlAB-lacZ fusion could be partially restored by the addition of synthetic C4-HSL and Pseudomonas quinolone signal (PQS). It is proposed that the MexEF-OprN efflux pump affects intracellular PQS levels.Pseudomonas aeruginosa is an opportunistic pathogen which may cause pneumonia and bacteremia in immunocompromised hosts and is responsible for chronic destructive lung disease in patients suffering from cystic fibrosis. The pathogenicity of P. aeruginosa is attributable to an arsenal of virulence factors, some of which are cell associated (pili, nonpilus adhesins, lipopolysaccharide, and alginate) while others are secreted (proteases, rhamnolipids, exotoxin A, exoenzyme S, and pyocyanin). The production of many of these extracellular virulence factors is controlled by two cell-to-cell signaling systems, called las and rhl, which are both composed of a transcriptional regulator (LasR and RhlR, respectively) and an autoinducer synthase (LasI and RhlI, respectively). LasI and RhlI catalyze the last step in the synthesis of the cell-to-cell signaling molecules 3-oxo-C12-homoserine lactone (3-oxo-C12-HSL) and C4-HSL, respectively; each of these molecules binds to, and activates, its corresponding transcriptional regulator. The systems are connected via a hierarchical cascade (19) and allow coordinated production of extracellular virulence factors, which occurs only when the bacterial cell density has reached a threshold (quorum). Recently, a novel signaling molecule, called PQS, for Pseudomonas quinolone signal (39), has been identified. Furthermore, the published genome sequence of PAO1 (53) has revealed a new modulator of cellto-cell signaling, termed QscR (4). This protein is homologous to both LasR and RhlR and seems to prevent premature transcription of quorum-sensing regulated genes.Besides its pathogenic capabilities, P. aeruginosa is well known for its intrinsic resistance to a wide range of antimicrobial agents and its ability to develop multidrug resistance following antibi...

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Cloning and nucleotide sequence of the Pseudomonas aeruginosa nfxB gene, conferring resistance to new quinolones

Cited by 29 publications

References 14 publications

ThepqrABOperon Is Responsible for Paraquat Resistance inStreptomyces coelicolor

ThepqrABOperon Is Responsible for Paraquat Resistance inStreptomyces coelicolor

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

Overexpression of the MexEF-OprN Multidrug Efflux System Affects Cell-to-Cell Signaling in Pseudomonas aeruginosa

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