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

Cited by 3 publications

References 29 publications

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Mechanisms of Resistance to Antibacterial Agents

Bradford,

Castanheira

2023

ClinMicroNow

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Bacterial pathogens have developed resistance to antibacterial agents via multiple routes. The emergence of antimicrobial resistance phenotypes is directly linked to the use of any given anti microbial agent. Resistance to aminoglycosides occurs by several different mechanisms that can coexist in the same bacterial cell. β‐Lactam antibiotics act by inhibiting penicillin‐binding proteins, which are transpeptidases and transglycosylases that synthesize the peptidogly can that composes the bacterial cell wall. The main bacterial resistance mechanism against fluoroquinolonesis is the alteration of their target in the deoxyribonucleic acid synthesis process. Tetracyclines are bacteriostatic antibiotics that inhibit bacterial growth by binding to the ribosome, thereby preventing protein synthesis. Nitrofurantoin is a synthetic antibacterial agent that is only used in the treatment of urinary tract infections. Rifampin is particularly active against Gram‐positive bacteria and mycobacteria. Daptomycin is a cyclic lipopeptide antibiotic with activity exclusively against Gram‐positive bacteria.

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Mechanisms of Resistance to Antibacterial Agents

Bradford,

Castanheira

2023

ClinMicroNow

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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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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 3 publications

References 29 publications

Mechanisms of Resistance to Antibacterial Agents

Mechanisms of Resistance to Antibacterial Agents

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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