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Publication Abstract from PubMed

Klebsiella pneumoniae carbapenemase-2 (KPC-2) presents a clinical threat as this beta-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 beta-lactam and the beta-lactamase inhibitor yet has lowered minimum inhibitory concentrations for all other beta-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 Omega loop. These results could explain why the KPC-2 D179Y variant, which has a disordered Omega 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 degrees 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 beta-lactamase inhibitors.

Exploring avibactam and relebactam inhibition of Klebsiella pneumoniae carbapenemase D179N variant: role of the Omega loop-held deacylation water.,Alsenani TA, Viviani SL, Papp-Wallace KM, Bonomo RA, van den Akker F Antimicrob Agents Chemother. 2023 Oct 18;67(10):e0035023. doi: , 10.1128/aac.00350-23. Epub 2023 Sep 26. PMID:37750722^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.