A Two Amino Acid Duplication, L167E168, in the Ω-Loop Drastically Decreases Carbapenemase Activity of KPC-53, a Natural Class A β-Lactamase

Piccirilli, Alessandra; Cherubini, Sabrina; Celenza, Giuseppe; Rossolini, Gian María; Brisdelli, Fabrizia; Segatore, Bernardetta; Principe, Luigi; Luzzaro, Francesco; Andriani, Lilia; Amicosante, Gianfranco; Perilli, Mariagrazia

doi:10.1128/aac.02402-21

Antimicrob Agents Chemother

2022

DOI: 10.1128/aac.02402-21

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A Two Amino Acid Duplication, L167E168, in the Ω-Loop Drastically Decreases Carbapenemase Activity of KPC-53, a Natural Class A β-Lactamase

Alessandra Piccirilli

Sabrina Cherubini

Giuseppe Celenza

et al.

Abstract: KPC-53 enzyme is a natural KPC variant which showed a duplication of L167E168 residues in the Ω-loop structure. The bla KPC-53 gene was cloned both into pBC-SK and pET-24a vectors, and the recombinant plasmids were transferred by transformation in Escherichia coli competent cells to evaluate the antimicrobial susceptibility and to produce the enzyme.

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Cited by 2 publications

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Exploring avibactam and relebactam inhibition of Klebsiella pneumoniae carbapenemase D179N variant: role of the Ω loop-held deacylation water

Alsenani,

Viviani,

Papp-Wallace

et al. 2023

Antimicrob Agents Chemother

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Klebsiella pneumoniae carbapenemase-2 (KPC-2) presents a clinical threat as this β-lactamase confers resistance to carbapenems. Recent variants of KPC-2 in clinical isolates contribute to concerning resistance phenotypes. Klebsiella pneumoniae expressing KPC-2 D179Y acquired resistance to the ceftazidime/avibactam combination affecting both the β-lactam and the β-lactamase inhibitor yet has lowered minimum inhibitory concentrations for all other β-lactams tested. Furthermore, Klebsiella pneumoniae expressing the KPC-2 D179N variant also manifested resistance to ceftazidime/avibactam yet retained its ability to confer resistance to carbapenems although significantly reduced. This structural study focuses on the inhibition of KPC-2 D179N by avibactam and relebactam and expands our previous analysis that examined ceftazidime resistance conferred by D179N and D179Y variants. Crystal structures of KPC-2 D179N soaked with avibactam and co-crystallized with relebactam were determined. The complex with avibactam reveals avibactam making several hydrogen bonds, including with the deacylation water held in place by Ω loop. These results could explain why the KPC-2 D179Y variant, which has a disordered Ω loop, has a decreased affinity for avibactam. The relebactam KPC-2 D179N complex revealed a new orientation of the diazabicyclooctane (DBO) intermediate with the scaffold piperidine ring rotated ~150° from the standard DBO orientation. The density shows relebactam to be desulfated and present as an imine-hydrolysis intermediate not previously observed. The tetrahedral imine moiety of relebactam interacts with the deacylation water. The rotated relebactam orientation and deacylation water interaction could potentially contribute to KPC-mediated DBO fragmentation. These results elucidate important differences that could aid in the design of novel β-lactamase inhibitors.

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Exploring avibactam and relebactam inhibition of Klebsiella pneumoniae carbapenemase D179N variant: role of the Ω loop-held deacylation water

Alsenani,

Viviani,

Papp-Wallace

et al. 2023

Antimicrob Agents Chemother

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Klebsiella pneumoniae carbapenemase variants: the new threat to global public health

Ding,

Shen,

Chen

et al. 2023

Clin Microbiol Rev

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SUMMARY Klebsiella pneumoniae carbapenemase (KPC) variants, which refer to the substitution, insertion, or deletion of amino acid sequence compared to wild bla KPC type, have reduced utility of ceftazidime-avibactam (CZA), a pioneer antimicrobial agent in treating carbapenem-resistant Enterobacterales infections. So far, more than 150 bla KPC variants have been reported worldwide, and most of the new variants were discovered in the past 3 years, which calls for public alarm. The KPC variant protein enhances the affinity to ceftazidime and weakens the affinity to avibactam by changing the KPC structure, thereby mediating bacterial resistance to CZA. At present, there are still no guidelines or expert consensus to make recommendations for the diagnosis and treatment of infections caused by KPC variants. In addition, meropenem-vaborbactam, imipenem-relebactam, and other new β-lactam-β-lactamase inhibitor combinations have little discussion on KPC variants. This review aims to discuss the clinical characteristics, risk factors, epidemiological characteristics, antimicrobial susceptibility profiles, methods for detecting bla KPC variants, treatment options, and future perspectives of bla KPC variants worldwide to alert this new great public health threat.

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A Two Amino Acid Duplication, L167E168, in the Ω-Loop Drastically Decreases Carbapenemase Activity of KPC-53, a Natural Class A β-Lactamase

Cited by 2 publications

References 29 publications

Exploring avibactam and relebactam inhibition of Klebsiella pneumoniae carbapenemase D179N variant: role of the Ω loop-held deacylation water

Exploring avibactam and relebactam inhibition of Klebsiella pneumoniae carbapenemase D179N variant: role of the Ω loop-held deacylation water

Klebsiella pneumoniae carbapenemase variants: the new threat to global public health

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