Brunetti, Florencia;
Gutkind, Gabriel;
Gao, Lin;
Haider, Shozeb;
Bonomo, Robert A;
Power, Pablo;
(2025)
Impact of the double deletion ΔG242-T243 in KPC-2 in the effectiveness of ceftazidime-avibactam and imipenem-relebactam.
Antimicrobial Agents and Chemotherapy
, 69
(6)
, Article e0191524. 10.1128/aac.01915-24.
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Abstract
Combinations of β-lactam-diazabicyclooctane inhibitors (DBOs) like ceftazidime-avibactam (CZA) and imipenem-relebactam (IMR) have shown efficacy in treating KPC-2-producing Klebsiella pneumoniae. However, CZA-resistant K. pneumoniae strains have been identified, often linked to substitutions and/or insertions/deletions in three different loops of KPC: (i) the Ω-loop region (amino acids 164-179), (ii) the 237-243 loop; and (iii) the 266-275 loop. This study investigates the impact of the double deletion ΔG242-T243 present in KPC-14. Our results demonstrate that the lower effectiveness of CZA against KPC-14 can be explained by both increased hydrolysis of ceftazidime and a lower affinity and acylation rate by avibactam. In contrast, the IMR combination was efficient in restoring susceptibility to the KPC-14 producing-clone. Although we also observed a lower affinity and acylation rate for relebactam in KPC-14, this reduction in affinity was accompanied by a loss in the carbapenemase activity, finally resulting in an IMR susceptibility phenotype for KPC-14. Expansion of the substrate profile of KPC-14 toward ceftazidime is associated with a trade-off for carbapenems, other penicillins, and cephalosporins, as well as a higher inhibition by clavulanic acid compared to KPC-2. This study provides a better understanding of how deletions in the 237-243 loop affect the effectiveness of novel DBO-combinations and supports the hypothesis that these mutations result in CZA resistance by other different biochemical mechanisms than mutations in the Ω-loop.
| Type: | Article |
|---|---|
| Title: | Impact of the double deletion ΔG242-T243 in KPC-2 in the effectiveness of ceftazidime-avibactam and imipenem-relebactam |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1128/aac.01915-24 |
| Publisher version: | https://doi.org/10.1128/aac.01915-24 |
| Language: | English |
| Additional information: | © 2025 Brunetti et al. This is an openaccess article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/). |
| Keywords: | KPC-14, CZA, DBO, Klebsiella pneumoniae, avibactam, relebactam |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy > Pharma and Bio Chemistry |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10209775 |
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