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Int J Antimicrob Agents. 2019 May;53(5):620-628. doi: 10.1016/j.ijantimicag.2019.01.009. Epub 2019 Jan 19.

Penicillin-binding protein 3 is a common adaptive target among Pseudomonas aeruginosa isolates from adult cystic fibrosis patients treated with β-lactams.

Author information

1
Toronto General Hospital Research Institute, University Health Network, Toronto, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada.
2
Toronto General Hospital Research Institute, University Health Network, Toronto, Canada.
3
Centre for the Analysis of Genome Evolution and Function, University of Toronto, Toronto, Canada.
4
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada; Department of Pediatrics, Division of Infectious Diseases, The Hospital for Sick Children, Toronto, Canada.
5
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada; Department of Pediatric Laboratory Medicine, Division of Microbiology, The Hospital for Sick Children, Toronto, Canada.
6
Toronto Adult Cystic Fibrosis Centre, St Michael's Hospital, Toronto, Canada.
7
Centre for the Analysis of Genome Evolution and Function, University of Toronto, Toronto, Canada; Department of Cell & Systems Biology, University of Toronto, Toronto, Canada.
8
Toronto General Hospital Research Institute, University Health Network, Toronto, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada; Department of Laboratory Medicine & Molecular Diagnostics, Sunnybrook Health Sciences Centre, Toronto, Canada. Electronic address: david.hwang@sunnybrook.ca.

Abstract

OBJECTIVE:

Determining the mechanisms that modulate β-lactam resistance in clinical Pseudomonas aeruginosa (P. aeruginosa) isolates can be challenging, as the molecular profiles identified in mutation-based or expression-based resistance determinant screens may not correlate with in vitro phenotypes. One of the lesser studied resistance mechanisms in P. aeruginosa is the modification of penicillin-binding protein 3 (pbpB/ftsI). This study reported that nonsynonymous polymorphisms within pbpB frequently occur among β-lactam resistant sputum isolates, and are associated with unique antibiotic susceptibility patterns.

METHODS:

Longitudinally collected isolates (n = 126) from cystic fibrosis (CF) patients with or without recent β-lactam therapy or of non-clinical origin were tested for susceptibility to six β-lactams (aztreonam, ceftazidime, cefsulodin, cefepime, meropenem, and piperacillin). Known β-lactam resistance mechanisms were characterised by polymerase chain reaction (PCR)-based methods, and polymorphisms in the transpeptidase-encoding domain of pbpB identified by sequencing.

RESULTS:

Twelve nonsynonymous polymorphisms were detected among 86 isolates (67%) from five CF patients with a history of β-lactam therapy, compared with one polymorphism in 30 (3.3%) from three patients who had not received β-lactam treatments. No nonsynonymous polymorphisms were found in ten environmental isolates. Multiple pbpB alleles, often with different combinations of polymorphisms, were detected within the population of strains from each CF patient for up to 2.6 years. Traditional patterns of ampC or mexA de-repression reduced expression of oprD or the presence of extended-spectrum β-lactamases were not observed in resistant isolates with nonsynonymous polymorphisms in pbpB.

CONCLUSION:

This study's findings suggest that pbpB is a common adaptive target, and may contribute to the development of β-lactam resistance in P. aeruginosa.

KEYWORDS:

Antimicrobial susceptibility; Cystic fibrosis; Penicillin-binding protein 3; Pseudomonas aeruginosa; β-lactam resistance

[Indexed for MEDLINE]

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