期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 215, 期 -, 页码 -出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2021.113257
关键词
Antimicrobial resistance; beta-Lactams; Penems Carbapenems; Serine-beta-lactamases; Metallo-beta-lactamases
资金
- Medical Research Council MRC [MR/T016035/1]
- National Institute of Allergy and Infectious Diseases of the National Institutes of Health (NIH) [R01AI100560]
- Wellcome Trust
- BBSRC [BB/M011224/1]
- Deutsche Akademie fur Naturforscher Leopoldina, Germany
- Wellcome Investigator Award in Science [210734/Z/18/Z]
- Royal Society Wolfson Fellowship [RSWFR2182017]
- Science & Technologies Facilities Council/UK Research and Innovation
- EPSRC
- Wellcome Trust [210734/Z/18/Z] Funding Source: Wellcome Trust
- MRC [MR/T016035/1] Funding Source: UKRI
Penems have shown potential as antibacterials and beta-lactamase inhibitors, but their clinical use is limited compared to carbapenems. Faropenem, with a C-2 tetrahydrofuran ring, is resistant to some beta-lactamases. Studies on reactions of faropenem with beta-lactamases demonstrate different outcomes, suggesting further research is needed for optimizing the interactions between penems and beta-lactamases.
Penems have demonstrated potential as antibacterials and beta-lactamase inhibitors; however, their clinical use has been limited, especially in comparison with the structurally related carbapenems. Faropenem is an orally active antibiotic with a C-2 tetrahydrofuran (THF) ring, which is resistant to hydrolysis by some beta-lactamases. We report studies on the reactions of faropenem with carbapenem-hydrolysing b-lactamases, focusing on the class A serine beta-lactamase KPC-2 and the metallo beta-lactamases (MBLs) VIM-2 (a subclass B1 MBL) and L1 (a B3 MBL). Kinetic studies show that faropenem is a substrate for all three blactamases, though it is less efficiently hydrolysed by KPC-2. Crystallographic analyses on faropenemderived complexes reveal opening of the beta-lactam ring with formation of an imine with KPC-2, VIM-2, and L1. In the cases of the KPC-2 and VIM-2 structures, the THF ring is opened to give an alkene, but with L1 the THF ring remains intact. Solution state studies, employing NMR, were performed on L1, KPC-2, VIM-2, VIM-1, NDM-1, OXA-23, OXA-10, and OXA-48. The solution results reveal, in all cases, formation of imine products in which the THF ring is opened; formation of a THF ring-closed imine product was only observed with VIM- 1 and VIM-2. An enamine product with a closed THF ring was also observed in all cases, at varying levels. Combined with previous reports, the results exemplify the potential for different outcomes in the reactions of penems with MBLs and SBLs and imply further structure-activity relationship studies are worthwhile to optimise the interactions of penems with beta-lactamases. They also exemplify how crystal structures of beta-lactamase substrate/inhibitor complexes do not always reflect reaction outcomes in solution. (C) 2021 Published by Elsevier Masson SAS.
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