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Increased expression of Qnr is sufficient to confer clinical resistance to ciprofloxacin in Escherichia coli.


ABSTRACT:

Background

Ciprofloxacin, a fluoroquinolone, targets two essential bacterial enzymes, DNA gyrase and topoisomerase IV. Plasmid-borne qnr genes, encoding proteins that protect DNA gyrase and topoisomerase IV from inhibition by fluoroquinolones, contribute to resistance development. However, the presence of a plasmid-borne qnr gene alone is insufficient to confer clinical resistance.

Objectives

We asked whether the level of expression of qnr was a limiting factor in its ability to confer clinical resistance and whether expression could be increased without reducing fitness or viability.

Methods

qnrB and qnrS were recombineered onto the chromosome of Escherichia coli under the control of constitutive promoters of various strengths. Expression was measured by qPCR, MIC and relative fitness as a function of expression level were determined.

Results

For both qnr genes there was a positive relationship between the level of qnr mRNA and the MIC of ciprofloxacin. The highest MICs achieved with qnrB or qnrS as the sole resistance determinant were 0.375 and 1?mg/L, respectively, and were reached at expression levels that did not affect growth rate or viability. The qnrS-mediated MIC is above the EUCAST clinical breakpoint for resistance to ciprofloxacin. In the absence of Lon protease activity, overexpression of qnr genes was associated with high fitness cost, possibly explaining observations of toxicity in other genetic backgrounds.

Conclusions

The ability to generate a high MIC without incurring a fitness cost shows that, in an appropriate genetic context, qnrS has the potential to generate clinical resistance to ciprofloxacin in one step.

SUBMITTER: Garoff L 

PROVIDER: S-EPMC5890660 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Publications

Increased expression of Qnr is sufficient to confer clinical resistance to ciprofloxacin in Escherichia coli.

Garoff Linnéa L   Yadav Kavita K   Hughes Diarmaid D  

The Journal of antimicrobial chemotherapy 20180201 2


<h4>Background</h4>Ciprofloxacin, a fluoroquinolone, targets two essential bacterial enzymes, DNA gyrase and topoisomerase IV. Plasmid-borne qnr genes, encoding proteins that protect DNA gyrase and topoisomerase IV from inhibition by fluoroquinolones, contribute to resistance development. However, the presence of a plasmid-borne qnr gene alone is insufficient to confer clinical resistance.<h4>Objectives</h4>We asked whether the level of expression of qnr was a limiting factor in its ability to c  ...[more]

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