Open AccessEffect of Ciprofloxacin Concentration on the Frequency and Nature of Resistant Mutants Selected from Pseudomonas aeruginosa mutS and mutT Hypermutators
Author(s) -
Natalia Rosalía Morero,
Mariela Roxana Monti,
Carlos E. Argaraña
Publication year - 2011
Publication title -
antimicrobial agents and chemotherapy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.07
H-Index - 259
eISSN - 1070-6283
pISSN - 0066-4804
DOI - 10.1128/aac.01826-10
Subject(s) - pseudomonas aeruginosa , efflux , mutant , biology , microbiology and biotechnology , wild type , context (archaeology) , ciprofloxacin , mutagen , mutation , repressor , escherichia coli , multiple drug resistance , genetics , antibiotics , bacteria , dna , gene , gene expression , paleontology
The rapid emergence of drug resistance upon treatment ofPseudomonas aeruginosa infections with fluoroquinolones is a serious concern. In this study, we report the effect of hypermutability on the mutant selection window for ciprofloxacin (CIP) by comparing the hypermutator MPAO1mutS andmutT strains with the wild-type strain. The mutant selection window was shifted to higher CIP concentrations for both hypermutators, presenting themutS strain with a broader selection window in comparison to the wild-type strain. The mutation prevention concentrations (MPC) determined formutT andmutS strains were increased 2- and 4-fold over the wild-type level, respectively. In addition, we analyzed the molecular bases for resistance in the bacterial subpopulations selected at different points in the window. At the top of the window, the resistant clones isolated were mainly mutated in GyrA and ParC topoisomerase subunits, while at the bottom of the window, resistance was associated with the overexpression of MexCD-OprJ and MexAB-OprM efflux pumps. Accordingly, a greater proportion of multidrug-resistant clones were found among the subpopulations isolated at the lower CIP concentrations. Furthermore, we found that the exposure to CIP subinhibitory concentrations favors the accumulation of cells overexpressing MexCD-OprJ (due to mutations in the transcriptional repressor NfxB) and MexAB-OprM efflux pumps. We discuss these results in the context of the possible participation of this antibiotic in a mutagenic process.