Aminoglycoside resistance of Pseudomonas aeruginosa in cystic fibrosis results from convergent evolution in the mexZ gene

Michelle Prickett, Alan R Hauser, Susanna A McColley, Joanne Cullina, Eileen Potter, Cathy Powers, Manu Jain*

*Corresponding author for this work

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Rationale Aminoglycoside (AG) resistance of Pseudomonas aeruginosa in cystic fibrosis (CF) is associated with poorer clinical outcomes and is usually due to overexpression of the efflux pump MexXY. MexXY is regulated by mexZ, one of the most commonly mutated genes in CF P. aeruginosa isolates. Little is known about the evolutionary relationship between AG resistance, MexXY expression and mexZ mutations. Objectives To test the hypothesis that AG resistance in P. aeruginosa develops in parallel with higher MexXY expression and mexZ mutations. Methods CF P. aeruginosa isolates were compared for chronically infected (CI) adults, CI children and children with new infection. Measurements One P. aeruginosa isolate from each patient was analysed for mexZ mutations, mexY mRNA expression and amikacin resistance. Main results 56 patients with CF were enrolled: 21 children with new P. aeruginosa infection, 18 CI children and 17 CI adults. Amikacin resistance and mexY mRNA expression were higher in cohorts with longer P. aeruginosa infection. The prevalence of non-conservative mexZ mutations was 0%, 33% and 65% in children with new infection, CI children and CI adults, respectively. The same trend was seen in the ratio of non-conservative to non-synonymous mexZ mutations. Of isolates with non-conservative mexZ mutations, 59% were amikacin-resistant compared with 18% of isolates with non-synonymous mutations. The doubling rate of amikacin resistance and non-conservative mexZ mutations was approximately 5 years. Conclusions P. aeruginosa mexZ mutations undergo positive selection resulting in increased mexY mRNA expression and amikacin resistance and likely play a role in bacterial adaption in the CF lung.

Original languageEnglish (US)
Pages (from-to)40-47
Number of pages8
JournalThorax
Volume72
Issue number1
DOIs
StatePublished - Jan 1 2017

Fingerprint

Aminoglycosides
Cystic Fibrosis
Pseudomonas aeruginosa
Amikacin
Mutation
Genes
Pseudomonas Infections
Messenger RNA
Infection
Lung

Keywords

  • Bacterial Infection
  • Bronchiectasis
  • Cystic Fibrosis
  • Respiratory Infection

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

Cite this

@article{b297149b726847c09cbc7c7dbf0d9fb4,
title = "Aminoglycoside resistance of Pseudomonas aeruginosa in cystic fibrosis results from convergent evolution in the mexZ gene",
abstract = "Rationale Aminoglycoside (AG) resistance of Pseudomonas aeruginosa in cystic fibrosis (CF) is associated with poorer clinical outcomes and is usually due to overexpression of the efflux pump MexXY. MexXY is regulated by mexZ, one of the most commonly mutated genes in CF P. aeruginosa isolates. Little is known about the evolutionary relationship between AG resistance, MexXY expression and mexZ mutations. Objectives To test the hypothesis that AG resistance in P. aeruginosa develops in parallel with higher MexXY expression and mexZ mutations. Methods CF P. aeruginosa isolates were compared for chronically infected (CI) adults, CI children and children with new infection. Measurements One P. aeruginosa isolate from each patient was analysed for mexZ mutations, mexY mRNA expression and amikacin resistance. Main results 56 patients with CF were enrolled: 21 children with new P. aeruginosa infection, 18 CI children and 17 CI adults. Amikacin resistance and mexY mRNA expression were higher in cohorts with longer P. aeruginosa infection. The prevalence of non-conservative mexZ mutations was 0{\%}, 33{\%} and 65{\%} in children with new infection, CI children and CI adults, respectively. The same trend was seen in the ratio of non-conservative to non-synonymous mexZ mutations. Of isolates with non-conservative mexZ mutations, 59{\%} were amikacin-resistant compared with 18{\%} of isolates with non-synonymous mutations. The doubling rate of amikacin resistance and non-conservative mexZ mutations was approximately 5 years. Conclusions P. aeruginosa mexZ mutations undergo positive selection resulting in increased mexY mRNA expression and amikacin resistance and likely play a role in bacterial adaption in the CF lung.",
keywords = "Bacterial Infection, Bronchiectasis, Cystic Fibrosis, Respiratory Infection",
author = "Michelle Prickett and Hauser, {Alan R} and McColley, {Susanna A} and Joanne Cullina and Eileen Potter and Cathy Powers and Manu Jain",
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Aminoglycoside resistance of Pseudomonas aeruginosa in cystic fibrosis results from convergent evolution in the mexZ gene. / Prickett, Michelle; Hauser, Alan R; McColley, Susanna A; Cullina, Joanne; Potter, Eileen; Powers, Cathy; Jain, Manu.

In: Thorax, Vol. 72, No. 1, 01.01.2017, p. 40-47.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Aminoglycoside resistance of Pseudomonas aeruginosa in cystic fibrosis results from convergent evolution in the mexZ gene

AU - Prickett, Michelle

AU - Hauser, Alan R

AU - McColley, Susanna A

AU - Cullina, Joanne

AU - Potter, Eileen

AU - Powers, Cathy

AU - Jain, Manu

PY - 2017/1/1

Y1 - 2017/1/1

N2 - Rationale Aminoglycoside (AG) resistance of Pseudomonas aeruginosa in cystic fibrosis (CF) is associated with poorer clinical outcomes and is usually due to overexpression of the efflux pump MexXY. MexXY is regulated by mexZ, one of the most commonly mutated genes in CF P. aeruginosa isolates. Little is known about the evolutionary relationship between AG resistance, MexXY expression and mexZ mutations. Objectives To test the hypothesis that AG resistance in P. aeruginosa develops in parallel with higher MexXY expression and mexZ mutations. Methods CF P. aeruginosa isolates were compared for chronically infected (CI) adults, CI children and children with new infection. Measurements One P. aeruginosa isolate from each patient was analysed for mexZ mutations, mexY mRNA expression and amikacin resistance. Main results 56 patients with CF were enrolled: 21 children with new P. aeruginosa infection, 18 CI children and 17 CI adults. Amikacin resistance and mexY mRNA expression were higher in cohorts with longer P. aeruginosa infection. The prevalence of non-conservative mexZ mutations was 0%, 33% and 65% in children with new infection, CI children and CI adults, respectively. The same trend was seen in the ratio of non-conservative to non-synonymous mexZ mutations. Of isolates with non-conservative mexZ mutations, 59% were amikacin-resistant compared with 18% of isolates with non-synonymous mutations. The doubling rate of amikacin resistance and non-conservative mexZ mutations was approximately 5 years. Conclusions P. aeruginosa mexZ mutations undergo positive selection resulting in increased mexY mRNA expression and amikacin resistance and likely play a role in bacterial adaption in the CF lung.

AB - Rationale Aminoglycoside (AG) resistance of Pseudomonas aeruginosa in cystic fibrosis (CF) is associated with poorer clinical outcomes and is usually due to overexpression of the efflux pump MexXY. MexXY is regulated by mexZ, one of the most commonly mutated genes in CF P. aeruginosa isolates. Little is known about the evolutionary relationship between AG resistance, MexXY expression and mexZ mutations. Objectives To test the hypothesis that AG resistance in P. aeruginosa develops in parallel with higher MexXY expression and mexZ mutations. Methods CF P. aeruginosa isolates were compared for chronically infected (CI) adults, CI children and children with new infection. Measurements One P. aeruginosa isolate from each patient was analysed for mexZ mutations, mexY mRNA expression and amikacin resistance. Main results 56 patients with CF were enrolled: 21 children with new P. aeruginosa infection, 18 CI children and 17 CI adults. Amikacin resistance and mexY mRNA expression were higher in cohorts with longer P. aeruginosa infection. The prevalence of non-conservative mexZ mutations was 0%, 33% and 65% in children with new infection, CI children and CI adults, respectively. The same trend was seen in the ratio of non-conservative to non-synonymous mexZ mutations. Of isolates with non-conservative mexZ mutations, 59% were amikacin-resistant compared with 18% of isolates with non-synonymous mutations. The doubling rate of amikacin resistance and non-conservative mexZ mutations was approximately 5 years. Conclusions P. aeruginosa mexZ mutations undergo positive selection resulting in increased mexY mRNA expression and amikacin resistance and likely play a role in bacterial adaption in the CF lung.

KW - Bacterial Infection

KW - Bronchiectasis

KW - Cystic Fibrosis

KW - Respiratory Infection

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