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

Autor:	Alsenani TA; Department of Biochemistry, Case Western Reserve University School of Medicine , Cleveland, Ohio, USA., Viviani SL; Department of Biochemistry, Case Western Reserve University School of Medicine , Cleveland, Ohio, USA., Papp-Wallace KM; Clinical Scientist Investigator, Louis Stokes Cleveland Department of Veterans Affairs Medical Center , North liberty, Iowa, USA., Bonomo RA; Department of Biochemistry, Case Western Reserve University School of Medicine , Cleveland, Ohio, USA.; Clinical Scientist Investigator, Louis Stokes Cleveland Department of Veterans Affairs Medical Center , North liberty, Iowa, USA.; Department of Medicine, Case Western Reserve University School of Medicine , Cleveland, Ohio, USA.; Department of Molecular Biology and Microbiology, Case Western Reserve University School of Medicine , Cleveland, Ohio, USA.; Department of Pharmacology, Case Western Reserve University School of Medicine , Cleveland, Ohio, USA.; Department of Proteomics and Bioinformatics, Case Western Reserve University School of Medicine , Cleveland, Ohio, USA.; CWRU-Cleveland VAMC Center for Antimicrobial Resistance and Epidemiology (Case VA CARES) , Cleveland, Ohio, USA., van den Akker F; Department of Biochemistry, Case Western Reserve University School of Medicine , Cleveland, Ohio, USA.
Jazyk:	angličtina
Zdroj:	Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 2023 Oct 18; Vol. 67 (10), pp. e0035023. Date of Electronic Publication: 2023 Sep 26.
DOI:	10.1128/aac.00350-23
Abstrakt:	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. Competing Interests: The authors declare no conflict of interest.
Databáze:	MEDLINE
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