Role of an mutation in multidrug resistance of -selected fluoroquinolone-resistant mutants of serovar Typhimurium

Olliver, Anne; Valle, Madeline E.; Chaslus-Dancla, Élisabeth; Cloeckaert, Axel

doi:10.1016/j.femsle.2004.07.046

Cited by 50 publications

(62 citation statements)

References 22 publications

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“…Mutations in acrR derepress expression of acrB, and acrS represses acrEF (96), giving rise to overexpression of the efflux pump. Such mutations have been found in acrR genes of clinical isolates of E. coli, S. enterica serovar Typhimurium, H. influenzae, and E. aerogenes (79,149,171,227) (Table 9). Webber, Talukder, and Piddock (228) confirmed that a substitution of Cys for Arg45 in AcrR of E. coli gave rise to increased expression of acrB, concomitant MDR, and low accumulated concentrations of ciprofloxacin in six isolates of E. coli.…”

Section: Mutations In the Local Repressor Genementioning

confidence: 99%

“…TolC, a 506-amino-acid protein, is also associated with AcrA (234). The substrate profile of the AcrAB-TolC pump includes chloramphenicol, lipophilic ␤-lactams, fluoroquinolones, tetracycline, rifampin, novobiocin, fusidic acid, nalidixic acid, ethidium bromide, acriflavine, bile salts, short-chain fatty acids, SDS, Triton X-100, and triclosan (46,139,149,216,230). In E. coli, acrD and the acrEF operon also encode efflux pumps (188,236), and AcrD has been shown to efflux aminoglycosides (140,188).…”

Section: Efflux Pumps Of Clinically Relevant Bacteria That Confer Mdrmentioning

confidence: 99%

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Clinically Relevant Chromosomally Encoded Multidrug Resistance Efflux Pumps in Bacteria

2006

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SUMMARY Efflux pump genes and proteins are present in both antibiotic-susceptible and antibiotic-resistant bacteria. Pumps may be specific for one substrate or may transport a range of structurally dissimilar compounds (including antibiotics of multiple classes); such pumps can be associated with multiple drug (antibiotic) resistance (MDR). However, the clinical relevance of efflux-mediated resistance is species, drug, and infection dependent. This review focuses on chromosomally encoded pumps in bacteria that cause infections in humans. Recent structural data provide valuable insights into the mechanisms of drug transport. MDR efflux pumps contribute to antibiotic resistance in bacteria in several ways: (i) inherent resistance to an entire class of agents, (ii) inherent resistance to specific agents, and (iii) resistance conferred by overexpression of an efflux pump. Enhanced efflux can be mediated by mutations in (i) the local repressor gene, (ii) a global regulatory gene, (iii) the promoter region of the transporter gene, or (iv) insertion elements upstream of the transporter gene. Some data suggest that resistance nodulation division systems are important in pathogenicity and/or survival in a particular ecological niche. Inhibitors of various efflux pump systems have been described; typically these are plant alkaloids, but as yet no product has been marketed.

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Section: Mutations In the Local Repressor Genementioning

confidence: 99%

Section: Efflux Pumps Of Clinically Relevant Bacteria That Confer Mdrmentioning

confidence: 99%

Clinically Relevant Chromosomally Encoded Multidrug Resistance Efflux Pumps in Bacteria

2006

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“…A domain homology search on the Pip sequence showed that Pip is homol- ogous to members of the TetR/AcrR family, which are transcriptional regulators (11). In E. coli, TetR regulates a pump involved in tetracycline resistance (3), and AcrR regulates a pump involved in multidrug resistance (26). A multiple alignment between Pip orthologues and the TetR N-terminal domain (Pfam 00440) shows that many amino acids are conserved within the region that contains a helix-turn-helix motif (Fig.…”

Section: General Characteristics Of Pip (I) Isolation Of Mutant Unabmentioning

confidence: 99%

Pip, a Novel Activator of Phenazine Biosynthesis in Pseudomonas chlororaphis PCL1391

et al. 2006

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Secondary metabolites are important factors for interactions between bacteria and other organisms. Pseudomonas chlororaphis PCL1391 produces the antifungal secondary metabolite phenazine-1-carboxamide (PCN) that inhibits growth of Fusarium oxysporum f. sp. radius lycopersici the causative agent of tomato foot and root rot. Our previous work unraveled a cascade of genes regulating the PCN biosynthesis operon, phzABCDEFGH. Via a genetic screen, we identify in this study a novel TetR/AcrR regulator, named Pip (phenazine inducing protein), which is essential for PCN biosynthesis. A combination of a phenotypical characterization of a pip mutant, in trans complementation assays of various mutant strains, and electrophoretic mobility shift assays identified Pip as the fifth DNA-binding protein so far involved in regulation of PCN biosynthesis. In this regulatory pathway, Pip is positioned downstream of PsrA (Pseudomonas sigma factor regulator) and the stationary-phase sigma factor RpoS, while it is upstream of the quorum-sensing system PhzI/PhzR. These findings provide further evidence that the path leading to the expression of secondary metabolism gene clusters in Pseudomonas species is highly complex.

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“…Overproduction of efflux pumps can occur via four mechanisms: (i) mutation of the local repressor gene (7,8), (ii) mutation in a global regulatory gene (9,10), (iii) mutation of the promoter region of the efflux pump gene (11), or (iv) insertion elements upstream of the transporter gene (12,13).…”

mentioning

confidence: 99%

AcrB drug-binding pocket substitution confers clinically relevant resistance and altered substrate specificity

Blair

Bavro

Ricci

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

164

165

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The incidence of multidrug-resistant bacterial infections is increasing globally and the need to understand the underlying mechanisms is paramount to discover new therapeutics. The efflux pumps of Gram-negative bacteria have a broad substrate range and transport antibiotics out of the bacterium, conferring intrinsic multidrug resistance (MDR). The genomes of pre-and posttherapy MDR clinical isolates of Salmonella Typhimurium from a patient that failed antibacterial therapy and died were sequenced. In the posttherapy isolate we identified a novel G288D substitution in AcrB, the resistance-nodulation division transporter in the AcrABTolC tripartite MDR efflux pump system. Computational structural analysis suggested that G288D in AcrB heavily affects the structure, dynamics, and hydration properties of the distal binding pocket altering specificity for antibacterial drugs. Consistent with this hypothesis, recreation of the mutation in standard Escherichia coli and Salmonella strains showed that G288D AcrB altered substrate specificity, conferring decreased susceptibility to the fluoroquinolone antibiotic ciprofloxacin by increased efflux. At the same time, the substitution increased susceptibility to other drugs by decreased efflux. Information about drug transport is vital for the discovery of new antibacterials; the finding that one amino acid change can cause resistance to some drugs, while conferring increased susceptibility to others, could provide a basis for new drug development and treatment strategies.efflux | antimicrobial resistance | AcrB | whole genome sequencing

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Role of an mutation in multidrug resistance of -selected fluoroquinolone-resistant mutants of serovar Typhimurium

Cited by 50 publications

References 22 publications

Clinically Relevant Chromosomally Encoded Multidrug Resistance Efflux Pumps in Bacteria

Clinically Relevant Chromosomally Encoded Multidrug Resistance Efflux Pumps in Bacteria

Pip, a Novel Activator of Phenazine Biosynthesis in Pseudomonas chlororaphis PCL1391

AcrB drug-binding pocket substitution confers clinically relevant resistance and altered substrate specificity

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