Genetic Features Leading to Reduced Susceptibility to Aztreonam-Avibactam among Metallo-β-Lactamase-Producing Escherichia coli Isolates

Metallo-β-lactamase (MBL)-producing <i>Escherichia coli</i> isolates resistant to the newly developed β-lactam/β-lactamase inhibitor drug combination aztreonam-avibactam (ATM-AVI) have been reported. Here, we analyzed a series of 118 clinical MBL-producing <i>E. coli</i> isolates of various geographical origins for susceptibility to ATM-AVI. The nature of the PBP3 protein sequence and the occurrence of <i>bla</i>_CMY genes for susceptibility to ATM-AVI were investigated. We showed here that elevated MICs of ATM-AVI among MBL-producing <i>E. coli</i> isolates resulted from a combination of different features, including modification of PBP3 protein sequence through specific amino acid insertions and production of CMY-type enzymes, particularly, CMY-42. We showed here that those insertions identified in the PBP3 sequence are not considered the unique basis of resistance to ATM-AVI, but they significantly contribute to it.