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Mechanism of plasmid-mediated quinolone resistance.

ABSTRACT: Quinolones are potent antibacterial agents that specifically target bacterial DNA gyrase and topoisomerase IV. Widespread use of these agents has contributed to the rise of bacterial quinolone resistance. Previous studies have shown that quinolone resistance arises by mutations in chromosomal genes. Recently, a multiresistance plasmid was discovered that encodes transferable resistance to quinolones. We have cloned the plasmid-quinolone resistance gene, termed qnr, and found it in an integron-like environment upstream from qacE Delta 1 and sulI. The gene product Qnr was a 218-aa protein belonging to the pentapeptide repeat family and shared sequence homology with the immunity protein McbG, which is thought to protect DNA gyrase from the action of microcin B17. Qnr had pentapeptide repeat domains of 11 and 28 tandem copies, separated by a single glycine with a consensus sequence of A/C D/N L/F X X. Because the primary target of quinolones is DNA gyrase in Gram-negative strains, we tested the ability of Qnr to reverse the inhibition of gyrase activity by quinolones. Purified Qnr-His(6) protected Escherichia coli DNA gyrase from inhibition by ciprofloxacin. Gyrase protection was proportional to the concentration of Qnr-His(6) and inversely proportional to the concentration of ciprofloxacin. The protective activity of Qnr-His(6) was lost by boiling the protein and involved neither quinolone inactivation nor independent gyrase activity. Protection of topoisomerase IV, a secondary target of quinolone action in E. coli, was not evident. How Qnr protects DNA gyrase and the prevalence of this resistance mechanism in clinical isolates remains to be determined.

SUBMITTER: Tran JH

PROVIDER: S-EPMC122823 | biostudies-literature | 2002 Apr

REPOSITORIES: biostudies-literature

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Mechanism of plasmid-mediated quinolone resistance.

Tran John H JH Jacoby George A GA

Proceedings of the National Academy of Sciences of the United States of America 20020409 8

Quinolones are potent antibacterial agents that specifically target bacterial DNA gyrase and topoisomerase IV. Widespread use of these agents has contributed to the rise of bacterial quinolone resistance. Previous studies have shown that quinolone resistance arises by mutations in chromosomal genes. Recently, a multiresistance plasmid was discovered that encodes transferable resistance to quinolones. We have cloned the plasmid-quinolone resistance gene, termed qnr, and found it in an integron-li ...[more]

PMID: 11943863

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Project description:A highly fluoroquinolone-resistant isolate of Aeromonas species was isolated from a wastewater treatment plant and found to possess multiple resistance mechanisms, including mutations in gyrA and parC, efflux pumps, and plasmid-mediated quinolone resistance (PMQR) genes. Complete sequencing of the IncU-type plasmid, pAC3, present in the strain revealed a circular plasmid DNA 15,872 bp long containing two PMQR genes [qnrS2 and aac(6')-Ib-cr]. A mobile insertion cassette element containing the qnrS2 gene and a typical miniature inverted-repeat transposable element (MITE) structure was identified in the plasmid. The present study revealed that this MITE sequence appears in other Aeromonas species plasmids and chromosomes. Plasmid pAC3 was introduced into Escherichia coli, and its PMQR genes were expressed, resulting in the acquisition of resistance. Proteome analysis of the recipient E. coli strain harboring the plasmid revealed that aac(6')-Ib-cr expression was constitutive and that qnrS2 expression was dependent upon fluoroquinolone stress through regulation by regulator of sigma D (Rsd). To the best of our knowledge, this is the first report to characterize a novel MITE sequence upstream of the PMQR gene within a mobile insertion cassette, as well as the regulation of qnrS2 expression. Our results suggest that this mobile element may play an important role in qnrS2 dissemination. IMPORTANCE In the present study, plasmid pAC3 isolated from a highly fluoroquinolone-resistant isolate of Aeromonas species was sequenced and found to contain two fluoroquinolone resistance genes, aac(6')-Ib-cr and qnrS2. Comparative analyses of plasmid pAC3 and other Aeromonas sp. IncU-type plasmids revealed a mobile insertion cassette element with a unique structure containing a qnrS2 gene and a typical miniature inverted-repeat transposable element (MITE) structure. This study also revealed that this MITE sequence appears in other Aeromonas species plasmids and chromosomes. Our results also demonstrate that the fluoroquinolone-dependent expression of qnrS2 is associated with rsd in E. coli DH5α harboring plasmid pAC3. Our findings suggest that the mobile element may play an important role in qnrS2 dissemination and that Aeromonas species constitute an important reservoir of fluoroquinolone resistance determinants in the environment.

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Mechanism of plasmid-mediated quinolone resistance.

Publications

Mechanism of plasmid-mediated quinolone resistance.

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