PMID:8524852

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
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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
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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 K_i 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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