Reduced susceptibility to aztreonam-avibactam conferred by acquired AmpC-type β-lactamases in PBP3-modified Escherichia coli.

Abstract

Carbapenemase-producingEnterobacterales are a growing threat, and very few therapeutic options remainactive against those multidrug resistant bacteria. Aztreonam is the molecule of choice against metallo-beta-lactamases (MBL)producers since it is not hydrolyzed by those enzymes, but the co-production of acquired plasmidic cephalosporinases orextended-spectrum β-lactamases leading to aztreonam resistance may reduce the efficacy of this molecule. Hence, thedevelopment of the aztreonam-avibactam (AZA) combination provides an interesting therapeutic alternative since avibactaminhibits the activity of both cephalosporinases and extended-spectrum β-lactamases. However, structural modifications ofpenicillin binding protein PBP3, the target of aztreonam, may lead to reduced susceptibility to aztreonam-avibactam. Here the impact of various plasmid-encoded AmpC-type β-lactamases (ACC-1, ACT-7, ACT-17, CMY-2, CMY-42,DHA-1, FOX-1, and FOX-5) on susceptibility to aztreonam-avibactam was evaluated using isogenic E. coli MG1655 strainsharboring insertions in PBP3 (YRIN and YRIK). The inhibitory activity of various β-lactamase inhibitors (clavulanic acid,tazobactam, avibactam, relebactam, and vaborbactam) were also compared against these enzymes. Hence, we showedthat reduced susceptibility to AZA was due to the combined effect of both AmpC production and amino acid insertions in PBP3.The highest resistance level was achieved in strains possessing the insertions in PBP3 in association with the production ofACT-7, ACC-1, or CMY-42. Although none of the recombinant strains tested displayed clinical resistance toaztreonam-avibactam, our data emphasize that the occurrence of such profile might be of clinical relevance for MBL-producingstrains.