NMR Backbone Assignment of VIM-2 and Identification of the Active Enantiomer of a Potential Inhibitor
(2022) In ACS Medicinal Chemistry Letters 13(2). p.257-261- Abstract
Carbapenem resistance caused by metallo-β-lactamases is a serious global challenge that, if not tackled efficiently, is expected to lead to millions of deaths in the coming decades. Verona-integron encoded metallo-β-lactamase 2 (VIM-2) is a bacterial enzyme that has been reported from multidrug-resistant nosocomial isolates of Pseudomonas aeruginosa and other Gram-negative pathogens. As it hydrolyzes most β-lactams efficiently, including carbapenems, it is a major threat to current antimicrobial chemotherapies. So far, there is no clinically applicable inhibitor for this enzyme. In this work, the backbone NMR resonance assignment of VIM-2 is disclosed, opening up NMR investigations of this clinically important enzyme and its potential... (More)
Carbapenem resistance caused by metallo-β-lactamases is a serious global challenge that, if not tackled efficiently, is expected to lead to millions of deaths in the coming decades. Verona-integron encoded metallo-β-lactamase 2 (VIM-2) is a bacterial enzyme that has been reported from multidrug-resistant nosocomial isolates of Pseudomonas aeruginosa and other Gram-negative pathogens. As it hydrolyzes most β-lactams efficiently, including carbapenems, it is a major threat to current antimicrobial chemotherapies. So far, there is no clinically applicable inhibitor for this enzyme. In this work, the backbone NMR resonance assignment of VIM-2 is disclosed, opening up NMR investigations of this clinically important enzyme and its potential inhibitors for solutions, enabling a rational improvement of inhibitor candidates. Making use of the assignment, we identified the active enantiomer of a VIM-2 inhibitor candidate as well as its possible binding site and Kd, utilizing NMR chemical shift titration experiments.
(Less)
- author
- publishing date
- 2022-02-10
- type
- Contribution to journal
- publication status
- published
- keywords
- antibiotic resistance, metallo-β-lactamase, NMR, VIM-2
- in
- ACS Medicinal Chemistry Letters
- volume
- 13
- issue
- 2
- pages
- 5 pages
- publisher
- The American Chemical Society (ACS)
- external identifiers
-
- scopus:85124280208
- scopus:85124280208
- ISSN
- 1948-5875
- DOI
- 10.1021/acsmedchemlett.1c00635
- language
- English
- LU publication?
- no
- id
- ad53b765-09b5-48d7-93df-35720171453c
- date added to LUP
- 2023-10-10 16:51:04
- date last changed
- 2023-11-16 17:32:06
@article{ad53b765-09b5-48d7-93df-35720171453c, abstract = {{<p>Carbapenem resistance caused by metallo-β-lactamases is a serious global challenge that, if not tackled efficiently, is expected to lead to millions of deaths in the coming decades. Verona-integron encoded metallo-β-lactamase 2 (VIM-2) is a bacterial enzyme that has been reported from multidrug-resistant nosocomial isolates of Pseudomonas aeruginosa and other Gram-negative pathogens. As it hydrolyzes most β-lactams efficiently, including carbapenems, it is a major threat to current antimicrobial chemotherapies. So far, there is no clinically applicable inhibitor for this enzyme. In this work, the backbone NMR resonance assignment of VIM-2 is disclosed, opening up NMR investigations of this clinically important enzyme and its potential inhibitors for solutions, enabling a rational improvement of inhibitor candidates. Making use of the assignment, we identified the active enantiomer of a VIM-2 inhibitor candidate as well as its possible binding site and Kd, utilizing NMR chemical shift titration experiments.</p>}}, author = {{Wieske, Lianne H.E. and Bogaerts, Jonathan and Leding, Albin A.M. and Wilcox, Scott and Andersson Rasmussen, Anna and Leszczak, Kinga and Turunen, Lotta and Herrebout, Wouter A. and Hubert, Madlen and Bayer, Annette and Erdélyi, Máté}}, issn = {{1948-5875}}, keywords = {{antibiotic resistance; metallo-β-lactamase; NMR; VIM-2}}, language = {{eng}}, month = {{02}}, number = {{2}}, pages = {{257--261}}, publisher = {{The American Chemical Society (ACS)}}, series = {{ACS Medicinal Chemistry Letters}}, title = {{NMR Backbone Assignment of VIM-2 and Identification of the Active Enantiomer of a Potential Inhibitor}}, url = {{http://dx.doi.org/10.1021/acsmedchemlett.1c00635}}, doi = {{10.1021/acsmedchemlett.1c00635}}, volume = {{13}}, year = {{2022}}, }