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Adaptation des Mécanismes de Résistance par Efflux Actif chez les Souches de Pseudomonas aeruginosa dans la Mucoviscidose

Abstract : Well known opportunistic bacterium Pseudomonas aeruginosa is a major player in chronic broncho-pulmonary infection that develops in patients with cystic fibrosis (CF). Through complex mechanisms, this pathogen is able to establish itself in the airways of patients and resist antibiotic treatments even more aggressive. Retrospective analysis of a collection of strains of Bacteriology laboratory of the University Hospital of Besançon found in most chronic carriers diversification sometimes extreme resistance patterns over time. The genotyping by microsatellite analysis (Multiple-Locus Variable-number tandem-repeat Analysis), the Single Nucleotide Polymorphisms sensing (flea Clondiag ®) and macrorestriction of genomic DNA (Pulsed-Field Gel Electrophoresis) led to similar results for the comparison of sequential isolates from the same patient. No clone was shared between the 6 patients, reflecting the absence of cross-contamination during the study period (1998-2006). The most common strain of primary colonization evolves to give rise to subpopulations with resistance levels fluctuate. If some of them are moving towards multidrug resistance, others, on the contrary, become hypersensitive to certain antibiotics. Thus, in nearly 30% of cases and in nearly one in two patients, strains become hypersensitive to β-lactam antibiotics. We have shown that this particular phenotype, named TicHS, among 11 isolates analyzed results from a deficiency in the active efflux system MexAB-OprM may involve either the sub-mexB gene expression (n = 2), the production a protein MexB (n = 2) or MEXA (n = 1) altered. In other isolates (n = 6), the MexAB-OprM system is a priori intact but non-functional. Moreover, in this work we have demonstrated, for the first time that P. aeruginosa can adapt to the in vivo pressure aminoglycosides modifying either the amount of efflux systems produced, but the pump itself. For example, the substitution in the protein F1018L MexY MexXY system (OprM) causes an increase in resistance by a factor of 2 vis-a-vis the substrates of the pump (aminoglycosides, cefepime, fluoroquinolones). However, this substitution only partially explains the high levels of resistance (MICs increased by a factor of 16) granted by the system MexXY (OprM) in some strains which suggests the presence of additional mechanisms may modulate the efficiency of this pump
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Lucie Vettoretti. Adaptation des Mécanismes de Résistance par Efflux Actif chez les Souches de Pseudomonas aeruginosa dans la Mucoviscidose. Bactériologie. Université de Franche-Comté, 2009. Français. ⟨NNT : 2009BESA0003⟩. ⟨tel-02104185⟩

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