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J Antimicrob Chemother. 2009 Feb;63(2):290-4. doi: 10.1093/jac/dkn480. Epub 2008 Nov 24.

The role of intra- and extragenic compensatory mutations in the suppression of fluoroquinolone resistance in a Salmonella Typhimurium gyrA mutant (D87G).

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  • 1Pharmaceutical Biology and Microbiology, Institute of Pharmacy, University of Hamburg, Bundesstrasse 45, D-20146 Hamburg, Germany.

Abstract

OBJECTIVES:

The live vaccine strain TAD Salmonella vacT (vacT) carrying gyrA mutations W59R, G75A, D87G and A866S shows resistance to nalidixic acid and rifampicin, but increased susceptibility to macrolides, fluoroquinolones and phenylalanyl-arginyl-beta-naphthylamide. This phenotype contrasts with the presence of the gyrA mutation D87G usually associated with reduced susceptibility to fluoroquinolones. Thus, a possible compensatory effect on the suppression of gyrA-mediated resistance by gyrA mutations within the quinolone resistance-determining region alone or in combination (intragenic) or by a mutation affecting AcrAB-TolC (extragenic), the major multidrug resistance efflux pump in Salmonella, was investigated.

METHODS:

Site-specifically introducing combinations of novel mutations into the chromosomal gyrA gene of the vacT parent strain M415 yielded defined gyrA mutants. These were characterized by determining fluoroquinolone susceptibilities and the degree of DNA supercoiling. DNA sequences of acrR, acrA and acrB of vacT were determined. A role of acrB mutations in increased fluoroquinolone susceptibility of vacT was investigated by a complementation test.

RESULTS:

All in vitro generated mutants carrying the gyrA D87G mutation showed increased fluoroquinolone MICs and reduced degrees of DNA supercoiling, irrespective of the presence of an additional gyrA mutation, W59R or G75A. DNA sequence analysis revealed two deletions in acrB of vacT. Complementation of vacT with an acrB wild-type gene decreased the susceptibilities to fluoroquinolones and macrolides.

CONCLUSIONS:

The increased fluoroquinolone susceptibility of the gyrA mutant vacT is most plausibly explained by a reduced efflux pump activity caused by acrB deletions in vacT.

PMID:
19033246
[PubMed - indexed for MEDLINE]
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