PMID:8524852

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Citation

Khodursky, AB, Zechiedrich, EL and Cozzarelli, NR (1995) Topoisomerase IV is a target of quinolones in Escherichia coli. Proc. Natl. Acad. Sci. U.S.A. 92:11801-5

Abstract

We have demonstrated that, in Escherichia coli, quinolone antimicrobial agents target topoisomerase IV (topo IV). The inhibition of topo IV becomes apparent only when gyrase is mutated to quinolone resistance. In such mutants, these antibiotics caused accumulation of replication catenanes, which is diagnostic of a loss of topo IV activity. Mutant forms of topo IV provided an additional 10-fold resistance to quinolones and prevented drug-induced catenane accumulation. Drug inhibition of topo IV differs from that of gyrase. (i) Wild-type topo IV is not dominant over the resistant allele. (ii) Inhibition of topo IV leads to only a slow stop in replication. (iii) Inhibition of topo IV is primarily bacteriostatic. These differences may result from topo IV acting behind the replication fork, allowing for repair of drug-induced lesions. We suggest that this and a slightly higher intrinsic resistance of topo IV make it secondary to gyrase as a quinolone target. Our results imply that the quinolone binding pockets of gyrase and topo IV are similar and that substantial levels of drug resistance require mutations in both enzymes.

Links

PubMed PMC40490

Keywords

Anti-Bacterial Agents/pharmacology; Ciprofloxacin; DNA Gyrase; DNA Replication/drug effects; DNA Topoisomerase IV; DNA Topoisomerases, Type II/drug effects; DNA Topoisomerases, Type II/genetics; DNA, Bacterial/metabolism; Dose-Response Relationship, Drug; Drug Resistance, Microbial; Escherichia coli/drug effects; Escherichia coli/enzymology; Mutation; Norfloxacin/pharmacology; Nucleic Acid Conformation; Quinolones/pharmacology

Main Points of the Paper

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Materials and Methods Used

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Phenotype Annotations

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Phenotype of Taxon Information Genotype Information (if known) Condition Information OMP ID OMP Term Name ECO ID ECO Term Name Notes Status

a mutation or genetic difference within a strain

  • Taxon: Escherichia coli
  • Strain: K-12
  • Substrain: 205096
  • NCBI Taxon ID: 83333
  • Genotype of Reference Strain: ParC+
  • Genotype of Experimental Strain : ParCL80
  • Reference Condition:
OMP:0006041

increased resistance to quinolone

ECO:0000178

in vivo assay evidence

The S80L mutation conferred an increase in resistance toward norfloxacin by about 10 fold. See table 3 for full experimental results. chEBI:100246

a mutation or genetic difference within a strain

  • Taxon: Escherichia coli
  • Strain: K-12
  • Substrain: 205096
  • NCBI Taxon ID: 83333
  • Genotype of Reference Strain: gyrA+
  • Genotype of Experimental Strain : gyrAR; S83L
  • Reference Condition:
OMP:0006041

increased resistance to quinolones

0000178

in vivo assay evidence

The mutation the gyrAr caused increased resistance to various quinolones. chEBI:23765

a mutation or genetic difference within a strain

  • Taxon: Escherichia coli
  • Strain: K-12
  • Substrain: 205096
  • NCBI Taxon ID: 83333
  • Genotype of Reference Strain: parC+ gyrA+
  • Genotype of Experimental Strain : parCL80 gyrAr
  • Reference Condition:
OMP:0006041

increased resistance to quinolones

ECO:0000178

in vivo assay evidence

the double parC and gyrA mutations conferred resistance to various quinolones at a rate that was 6 times higher than the strain with a single gyrAr mutation. See figure 4 for full experimental results. chEBI:23765

a mutation or genetic difference within a strain

  • Taxon: Escherichia coli
  • Strain: K-12
  • Substrain: 205096
  • NCBI Taxon ID: 83333
  • Genotype of Reference Strain: gyrA+ parC+
  • Genotype of Experimental Strain : gyrAr parCK
  • Reference Condition:
OMP:0006041

increased resistance to quinolone

ECO:0000178

in vivo assay evidence

The mutation conferred resistance toward quinolones at about 10 fold higher level than the gyrAr mutation alone and twice than parCL80 mutation. See figure 4. chEBI:23765


Notes

  • It was found that the tested drugs (nalidixic acid, ciprofloxacin, norfloxacin & various 2-pyridones) were 2 fold less effective on topo IV than on the gyrase despite their various Ki values. This indicates that the drugs were inhibitors of topo IV in vitro but none inhibited it preferentially.
  • Topo IV is a secondary to gyrase as a quinolone target.


        • The term for antimicrobial resistance is to be replaced with upcoming term

References

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