JAC Advance Access published online on March 6, 2008
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkn077
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Original research |
Low selection of topoisomerase mutants from strains of Escherichia coli harbouring plasmid-borne qnr genes
1 Université Paris12, IFR10, Créteil, France 2 AP-HP, CHU Henri Mondor, Service de Bactériologie-Virologie-Hygiène, Créteil, France 3 Hôpital d'Instruction des Armées Bégin Laboratoire de Biologie, Saint-Mandé, France 4 Ecole du Val de Grâce, Paris, France
Received 16 August 2007; returned 16 January 2008; revised 24 October 2007; accepted 5 February 2008
* Correspondence address. Laboratoire de Bactériologie-Virologie-Hygiène, CHU Henri Mondor, 51 rue du maréchal de Lattre de Tassigny, 94010 CRETEIL Cedex, France. Tel: +33-1-49812831; Fax: +33-1-49812839; E-mail: emmanuelle.cambau{at}hmn.aphp.fr
Objectives: To investigate mutations in the type II topoisomerase genes in quinolone-resistant mutants selected from bacteria harbouring plasmid-borne qnr genes.
Methods: Mutants were selected by nalidixic acid, ciprofloxacin and moxifloxacin from two Escherichia coli reference strains and corresponding transconjugants harbouring qnrA1, qnrA3, qnrB2 or qnrS1 genes.
Results: The proportion of resistant mutants selected by the three quinolones was, respectively, in the same range for qnr-positive transconjugants and reference strains. Only 20% (65/329) of the mutants selected from the transconjugants showed a gyrase mutation, whereas 79% (94/119) of those from the reference strains without a qnr gene did (P < 0.0001). At four times the MIC of the selector quinolone, gyrA mutants represented 49% and 95% of the mutants selected with nalidixic acid, 4% and 94% with ciprofloxacin and 0% and 54% with moxifloxacin for qnr-positive transconjugants and reference strains, respectively. Mutations within gyrA were distributed at codon 87 (D87G, H, N or Y) and at codon 83 (S83L) with three novel mutations (gyrA Ser83stop, gyrA Asp82Asn and gyrB insertion of Glu at 465) and three rare mutations (gyrA Gly81Asp, gyrA Asp82Gly and gyrA Ser431Pro), mainly obtained from reference strains after moxifloxacin selection. Strikingly, none of the mutants selected by moxifloxacin from qnr-positive transconjugants harboured a mutation in the topoisomerase genes.
Conclusions: Topoisomerase mutants are rarely selected by ciprofloxacin and moxifloxacin from strains harbouring qnr. This suggests that the quinolone resistance-determining region domains are protected from quinolones by the Qnr protein and consequently other mechanisms are developed to acquire a further step of fluoroquinolone resistance.
Key Words: quinolones , ciprofloxacin , gyrase , moxifloxacin , QRDR
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