Clark ST, Sinha U, Zhang Y, Wang PW, Donaldson SL, Coburn B, Waters VJ, Yau YCW, Tullis DE, Guttman DS, Hwang DM
Int. J. Antimicrob. Agents 2019 Jan;
PMID: 30664925
Abstract
Determining the mechanisms that modulate β-lactam resistance in clinical P. aeruginosa isolates can be challenging, as the molecular profiles identified in mutation- 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). Here, we report that nonsynonymous polymorphisms within pbpB frequently occur among β-lactam resistant sputum isolates, and are associated with unique antibiotic susceptibility patterns. 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 characterized by PCR-based methods, and polymorphisms in the transpeptidase-encoding domain of pbpB identified by sequencing. Twelve nonsynonymous polymorphisms were detected among 86 isolates (67%) from five CF patients with a history of β-lactam therapy, compared with only 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. Our findings suggest that pbpB is a common adaptive target, and may contribute to the development of β-lactam resistance in P. aeruginosa.