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

Objective: Determining the mechanisms that modulate beta-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 beta-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 beta-lactam therapy or of non-clinical origin were tested for susceptibility to six beta-lactams (aztreonam, ceftazidime, cefsulodin, cefepime, meropenem, and piperacillin). Known beta-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 beta-lactam therapy, compared with one polymorphism in 30 (3.3%) from three patients who had not received beta-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 beta-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 beta-lactam resistance in P. aeruginosa. (C) 2019 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.