Quantitative Contributions of Target Alteration and Decreased Drug Accumulation to Pseudomonas aeruginosa Fluoroquinolone Resistance.

2.50
Hdl Handle:
http://hdl.handle.net/10033/275612
Title:
Quantitative Contributions of Target Alteration and Decreased Drug Accumulation to Pseudomonas aeruginosa Fluoroquinolone Resistance.
Authors:
Bruchmann, Sebastian; Dötsch, Andreas; Nouri, Bianka; Chaberny, Iris F; Häussler, Susanne
Abstract:
Quinolone antibiotics constitute a clinically successful and widely used class of broad-spectrum antibiotics; however, the emergence and spread of resistance increasingly limits the use of fluoroquinolones in the treatment and management of microbial disease. In this study, we evaluated the quantitative contributions of quinolone target alteration and efflux pump expression to fluoroquinolone resistance in Pseudomonas aeruginosa. We generated isogenic mutations in hot spots of the quinolone resistance-determining regions (QRDRs) of gyrA, gyrB, and parC and inactivated the efflux regulator genes so as to overexpress the corresponding multidrug resistance (MDR) efflux pumps. We then introduced the respective mutations into the reference strain PA14 singly and in various combinations. Whereas the combined inactivation of two efflux regulator-encoding genes did not lead to resistance levels higher than those obtained by inactivation of only one efflux regulator-encoding gene, the combination of mutations leading to increased efflux and target alteration clearly exhibited an additive effect. This combination of target alteration and overexpression of efflux pumps was commonly observed in clinical P. aeruginosa isolates; however, these two mechanisms were frequently found not to be sufficient to explain the level of fluoroquinolone resistance. Our results suggest that there are additional mechanisms, independent of the expression of the MexAB-OprM, MexCD-OprJ, MexEF-OprN, and/or MexXY-OprM efflux pump, that increase ciprofloxacin resistance in isolates with mutations in the QRDRs.
Affiliation:
Department of Molecular Bacteriology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
Citation:
Quantitative Contributions of Target Alteration and Decreased Drug Accumulation to Pseudomonas aeruginosa Fluoroquinolone Resistance. 2013, 57 (3):1361-8 Antimicrob. Agents Chemother.
Journal:
Antimicrobial agents and chemotherapy
Issue Date:
Mar-2013
URI:
http://hdl.handle.net/10033/275612
DOI:
10.1128/AAC.01581-12
PubMed ID:
23274661
Type:
Article
Language:
en
ISSN:
1098-6596
Appears in Collections:
openaire; publications of the departmentment of molecular bacteriology(MOBA)

Full metadata record

DC FieldValue Language
dc.contributor.authorBruchmann, Sebastianen_GB
dc.contributor.authorDötsch, Andreasen_GB
dc.contributor.authorNouri, Biankaen_GB
dc.contributor.authorChaberny, Iris Fen_GB
dc.contributor.authorHäussler, Susanneen_GB
dc.date.accessioned2013-03-21T15:17:19Z-
dc.date.available2013-03-21T15:17:19Z-
dc.date.issued2013-03-
dc.identifier.citationQuantitative Contributions of Target Alteration and Decreased Drug Accumulation to Pseudomonas aeruginosa Fluoroquinolone Resistance. 2013, 57 (3):1361-8 Antimicrob. Agents Chemother.en_GB
dc.identifier.issn1098-6596-
dc.identifier.pmid23274661-
dc.identifier.doi10.1128/AAC.01581-12-
dc.identifier.urihttp://hdl.handle.net/10033/275612-
dc.description.abstractQuinolone antibiotics constitute a clinically successful and widely used class of broad-spectrum antibiotics; however, the emergence and spread of resistance increasingly limits the use of fluoroquinolones in the treatment and management of microbial disease. In this study, we evaluated the quantitative contributions of quinolone target alteration and efflux pump expression to fluoroquinolone resistance in Pseudomonas aeruginosa. We generated isogenic mutations in hot spots of the quinolone resistance-determining regions (QRDRs) of gyrA, gyrB, and parC and inactivated the efflux regulator genes so as to overexpress the corresponding multidrug resistance (MDR) efflux pumps. We then introduced the respective mutations into the reference strain PA14 singly and in various combinations. Whereas the combined inactivation of two efflux regulator-encoding genes did not lead to resistance levels higher than those obtained by inactivation of only one efflux regulator-encoding gene, the combination of mutations leading to increased efflux and target alteration clearly exhibited an additive effect. This combination of target alteration and overexpression of efflux pumps was commonly observed in clinical P. aeruginosa isolates; however, these two mechanisms were frequently found not to be sufficient to explain the level of fluoroquinolone resistance. Our results suggest that there are additional mechanisms, independent of the expression of the MexAB-OprM, MexCD-OprJ, MexEF-OprN, and/or MexXY-OprM efflux pump, that increase ciprofloxacin resistance in isolates with mutations in the QRDRs.en_GB
dc.language.isoenen
dc.relationinfo:eu-repo/grantAgreement/EC/FP7/260276/en
dc.rightsArchived with thanks to Antimicrobial agents and chemotherapyen_GB
dc.rightsopenAccessen
dc.titleQuantitative Contributions of Target Alteration and Decreased Drug Accumulation to Pseudomonas aeruginosa Fluoroquinolone Resistance.en
dc.typeArticleen
dc.contributor.departmentDepartment of Molecular Bacteriology, Helmholtz Centre for Infection Research, Braunschweig, Germany.en_GB
dc.identifier.journalAntimicrobial agents and chemotherapyen_GB

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