Antibiotic resistance in Pseudomonas aeruginosa strains with increased mutation frequency due to inactivation of the DNA oxidative repair system

L F Mandsberg; O Ciofu; N Kirkby; L E Christiansen; Henrik Enghusen Poulsen; N Høiby; Lotte Frigaard Mandsberg; Oana Ciofu; N Kirkby; L E Christiansen; H E Poulsen; N Høiby

doi:10.1128/AAC.00428-08

Antibiotic resistance in Pseudomonas aeruginosa strains with increased mutation frequency due to inactivation of the DNA oxidative repair system

L F Mandsberg, O Ciofu, N Kirkby, L E Christiansen, Henrik Enghusen Poulsen, N Høiby, Lotte Frigaard Mandsberg, Oana Ciofu, N Kirkby, L E Christiansen, H E Poulsen, N Høiby

67 Citations (Scopus)

Abstract

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 beta-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.

Original language	English
Journal	Antimicrobial Agents and Chemotherapy
Volume	53
Issue number	6
Pages (from-to)	2483-91
Number of pages	9
ISSN	0066-4804
DOIs	https://doi.org/10.1128/AAC.00428-08 https://doi.org/10.1128/AAC.00428-08
Publication status	Published - 1 Jun 2009

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Mandsberg, L. F., Ciofu, O., Kirkby, N., Christiansen, L. E., Poulsen, H. E., Høiby, N., Mandsberg, L. F., Ciofu, O., Kirkby, N., Christiansen, L. E., Poulsen, H. E., & Høiby, N. (2009). Antibiotic resistance in Pseudomonas aeruginosa strains with increased mutation frequency due to inactivation of the DNA oxidative repair system. Antimicrobial Agents and Chemotherapy, 53(6), 2483-91. https://doi.org/10.1128/AAC.00428-08, https://doi.org/10.1128/AAC.00428-08

Mandsberg, LF, Ciofu, O, Kirkby, N, Christiansen, LE, Poulsen, HE , Høiby, N, Mandsberg, LF, Ciofu, O, Kirkby, N, Christiansen, LE, Poulsen, HE & Høiby, N 2009, 'Antibiotic resistance in Pseudomonas aeruginosa strains with increased mutation frequency due to inactivation of the DNA oxidative repair system', Antimicrobial Agents and Chemotherapy, vol. 53, no. 6, pp. 2483-91. https://doi.org/10.1128/AAC.00428-08, https://doi.org/10.1128/AAC.00428-08

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title = "Antibiotic resistance in Pseudomonas aeruginosa strains with increased mutation frequency due to inactivation of the DNA oxidative repair system",

abstract = "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 beta-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.",

author = "Mandsberg, {L F} and O Ciofu and N Kirkby and Christiansen, {L E} and Poulsen, {Henrik Enghusen} and N H{\o}iby and Mandsberg, {Lotte Frigaard} and Oana Ciofu and N Kirkby and Christiansen, {L E} and Poulsen, {H E} and N H{\o}iby",

note = "Keywords: Cystic Fibrosis; DNA Repair; Drug Resistance, Bacterial; Humans; Microbial Sensitivity Tests; Mutation; Neutrophil Activation; Oxidation-Reduction; Oxidative Stress; Pseudomonas aeruginosa",

year = "2009",

month = jun,

day = "1",

doi = "10.1128/AAC.00428-08",

language = "English",

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pages = "2483--91",

journal = "Antimicrobial Agents and Chemotherapy",

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T1 - Antibiotic resistance in Pseudomonas aeruginosa strains with increased mutation frequency due to inactivation of the DNA oxidative repair system

AU - Mandsberg, L F

AU - Ciofu, O

AU - Kirkby, N

AU - Christiansen, L E

AU - Poulsen, Henrik Enghusen

AU - Høiby, N

AU - Mandsberg, Lotte Frigaard

AU - Ciofu, Oana

AU - Kirkby, N

AU - Christiansen, L E

AU - Poulsen, H E

AU - Høiby, N

N1 - Keywords: Cystic Fibrosis; DNA Repair; Drug Resistance, Bacterial; Humans; Microbial Sensitivity Tests; Mutation; Neutrophil Activation; Oxidation-Reduction; Oxidative Stress; Pseudomonas aeruginosa

PY - 2009/6/1

Y1 - 2009/6/1

N2 - 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 beta-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.

AB - 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 beta-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.

U2 - 10.1128/AAC.00428-08

DO - 10.1128/AAC.00428-08

M3 - Journal article

C2 - 19332676

SN - 0066-4804

VL - 53

SP - 2483

EP - 2491

JO - Antimicrobial Agents and Chemotherapy

JF - Antimicrobial Agents and Chemotherapy

IS - 6

ER -

Antibiotic resistance in Pseudomonas aeruginosa strains with increased mutation frequency due to inactivation of the DNA oxidative repair system

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