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The substitution N 132 G in the SDN motif of class A β-lactamases from rapidly growing mycobacteria was previously shown to impair their inhibition by avibactam but to improve the stability of acyl-enzymes formed with clavulanate. The same substitution was introduced in KPC-2 and CTX-M-15 to assess its impact on β-lactamases from Enterobacteriaceae and evaluate whether it may lead to resistance to the ceftazidime-avibactam combination. Kinetic parameters for the inhibition of the β-lactamases by avibactam and clavulanate were determined by spectrophotometry using nitrocefin as the substrate. The substitution N 132 G impaired (&gt;1,000-fold) the efficacy of carbamylation of KPC-2 and CTX-M-15 by avibactam. The substitution improved the inhibition of KPC-2 by clavulanate due to reduced deacylation, whereas the presence or absence of N 132 G resulted in the inhibition of CTX-M-15 by clavulanate. The hydrolysis of amoxicillin and nitrocefin by KPC-2 and CTX-M-15 was moderately affected by the substitution N 132 G, but that of ceftazidime, ceftaroline, and aztreonam was drastically reduced. Isogenic strains producing KPC-2 and CTX-M-15 were constructed to assess the impact of the substitution N 132 G on the antibacterial activities of β-lactam-inhibitor combinations. For amoxicillin, the substitution resulted in resistance and susceptibility for avibactam and clavulanate, respectively. For ceftazidime, ceftaroline, and aztreonam, the negative impact of the substitution on β-lactamase activity prevented resistance to the β-lactam-avibactam combinations. In conclusion, the N 132 G substitution has profound effects on the substrate and inhibition profiles of class A β-lactamases, which are largely conserved in distantly related enzymes. Fortunately, the substitution does not lead to resistance to the ceftazidime-avibactam combination.

antimicrobial agents and chemotherapy

Inhibition by Avibactam and Clavulanate of the β-Lactamases KPC-2 and CTX-M-15 Harboring the Substitution N <sup>132</sup> G in the Conserved SDN Motif

Inhibition by Avibactam and Clavulanate of the β-Lactamases KPC-2 and CTX-M-15 Harboring the Substitution N 132 G in the Conserved SDN Motif

Inhibition by Avibactam and Clavulanate of the β-Lactamases KPC-2 and CTX-M-15 Harboring the Substitution N ¹³² G in the Conserved SDN Motif