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



To test the hypothesis that AG resistance in P. aeruginosa develops in parallel with higher MexXY expression and mexZ mutations.



CF P. aeruginosa isolates were compared for chronically infected (CI) adults, CI children and children with new infection.



One P. aeruginosa isolate from each patient was analysed for mexZ mutations, mexY mRNA expression and amikacin resistance.



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.



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.
Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
Michelle H
MH
Prickett
Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
Alan R
AR
Hauser
Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.|Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, USA.
Susanna A
SA
McColley
Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, USA.
Joanne
J
Cullina
Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, USA.
Eileen
E
Potter
Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, USA.
Cathy
C
Powers
Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
Manu
M
Jain
D000293:Adolescent; D000328:Adult; D000583:Amikacin / Q000494:pharmacology*; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D017920:Antiporters / Q000235:genetics*; D001426:Bacterial Proteins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D002908:Chronic Disease; D003550:Cystic Fibrosis / Q000150:complications*; D024881:Drug Resistance, Bacterial / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008826:Microbial Sensitivity Tests; D009154:Mutation; D011552:Pseudomonas Infections / Q000188:drug therapy*; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D055815:Young Adult
D000900:Anti-Bacterial Agents; D017920:Antiporters; D001426:Bacterial Proteins; C402792:MexZ protein, Pseudomonas aeruginosa; D012333:RNA, Messenger; D000583:Amikacin
Bacterial Infection; Bronchiectasis; Cystic Fibrosis; Respiratory Infection