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Structural Basis of Reduced Susceptibility to Ceftazidime-Avibactam and Cefiderocol in Enterobacter cloacae Due to AmpC R2 Loop Deletion

Ceftazidime-avibactam and cefiderocol are two of the latest generation β-lactam agents that possess expanded activity against highly drug-resistant bacteria, including carbapenem-resistant Here, we show that structural changes in AmpC β-lactamases can confer reduced susceptibility to both agents. A...

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Published in:Antimicrobial agents and chemotherapy 2020-06, Vol.64 (7)
Main Authors: Kawai, Akito, McElheny, Christi L, Iovleva, Alina, Kline, Ellen G, Sluis-Cremer, Nicolas, Shields, Ryan K, Doi, Yohei
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cited_by cdi_FETCH-LOGICAL-a418t-4e2828e01620d69f73331a976f78fe8780e560fb371998c5a4381287c1b530e83
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container_issue 7
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container_title Antimicrobial agents and chemotherapy
container_volume 64
creator Kawai, Akito
McElheny, Christi L
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Shields, Ryan K
Doi, Yohei
description Ceftazidime-avibactam and cefiderocol are two of the latest generation β-lactam agents that possess expanded activity against highly drug-resistant bacteria, including carbapenem-resistant Here, we show that structural changes in AmpC β-lactamases can confer reduced susceptibility to both agents. A multidrug-resistant clinical strain (Ent385) was found to be resistant to ceftazidime-avibactam and cefiderocol without prior exposure to either agent. The AmpC β-lactamase of Ent385 (AmpC ) contained an alanine-proline deletion at positions 294 and 295 (A294_P295del) in the R2 loop. AmpC conferred reduced susceptibility to ceftazidime-avibactam and cefiderocol when cloned into TOP10. Purified AmpC showed increased hydrolysis of ceftazidime and cefiderocol compared to AmpC , in which the deletion was reverted. Comparisons of crystal structures of AmpC and AmpC , the canonical AmpC of complex, revealed that the two-residue deletion in AmpC induced drastic structural changes of the H-9 and H-10 helices and the R2 loop, which accounted for the increased hydrolysis of ceftazidime and cefiderocol. The potential for a single mutation in to confer reduced susceptibility to both ceftazidime-avibactam and cefiderocol requires close monitoring.
doi_str_mv 10.1128/AAC.00198-20
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source PubMed (Medline); American Society for Microbiology (ASM) Journals
subjects Anti-Bacterial Agents - pharmacology
Azabicyclo Compounds - pharmacology
beta-Lactamases - genetics
Cefiderocol
Ceftazidime - pharmacology
Cephalosporins
Drug Combinations
Enterobacter cloacae - genetics
Mechanisms of Resistance
Microbial Sensitivity Tests
title Structural Basis of Reduced Susceptibility to Ceftazidime-Avibactam and Cefiderocol in Enterobacter cloacae Due to AmpC R2 Loop Deletion
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