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Antimicrobial Agents and Chemotherapy, June 2009, p. 2483-2491, Vol. 53, No. 6
0066-4804/09/$08.00+0 doi:10.1128/AAC.00428-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
Antibiotic Resistance in Pseudomonas aeruginosa Strains with Increased Mutation Frequency Due to Inactivation of the DNA Oxidative Repair System
L. F. Mandsberg,1*
O. Ciofu,1
N. Kirkby,2
L. E. Christiansen,3
H. E. Poulsen,4,5 and
N. Høiby1,2
Department of International Health, Immunology, and Microbiology,1 Faculty of Health Sciences, University of Copenhagen,5 Department of Clinical Microbiology,2 Department of Clinical Pharmacology, Copenhagen University Hospital, Rigshospitalet, Copenhagen,4 Informatics and Mathematical Modelling, Technical University of Denmark, Lyngby, Denmark3
Received 1 April 2008/ Returned for modification 6 June 2008/ Accepted 19 February 2009
The chronic Pseudomonas aeruginosa infection of the lungs of cystic fibrosis (CF) patients is characterized by the biofilm mode of growth and chronic inflammation dominated by polymorphonuclear leukocytes (PMNs). A high percentage of P. aeruginosa strains show high frequencies of mutations (hypermutators [HP]). P. aeruginosa is exposed to oxygen radicals, both those generated by its own metabolism and especially those released by a large number of PMNs in response to the chronic CF lung infection. Our work therefore focused on the role of the DNA oxidative repair system in the development of HP and antibiotic resistance. We have constructed and characterized mutT, mutY, and mutM mutants in P. aeruginosa strain PAO1. The mutT and mutY mutants showed 28- and 7.5-fold increases in mutation frequencies, respectively, over that for PAO1. These mutators had more oxidative DNA damage (higher levels of 7,8-dihydro-8-oxodeoxyguanosine) than PAO1 after exposure to PMNs, and they developed resistance to antibiotics more frequently. The mechanisms of resistance were increased β-lactamase production and overexpression of the MexCD-OprJ efflux-pump. Mutations in either the mutT or the mutY gene were found in resistant HP clinical isolates from patients with CF, and complementation with wild-type genes reverted the phenotype. In conclusion, oxidative stress might be involved in the development of resistance to antibiotics. We therefore suggest the possible use of antioxidants for CF patients to prevent the development of antibiotic resistance.
* Corresponding author. Mailing address: Department of International Health, Immunology, and Microbiology, University of Copenhagen, Panum Institute, 24.1, Blegdamsvej 3, 2200N, Copenhagen, Denmark. Phone: 45 35 32 78 60. Fax: 45 35 32 76 93. E-mail: lomand{at}sund.ku.dk
Published ahead of print on 30 March 2009.
Antimicrobial Agents and Chemotherapy, June 2009, p. 2483-2491, Vol. 53, No. 6
0066-4804/09/$08.00+0 doi:10.1128/AAC.00428-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
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