Fluorinated Aliphatic Thiols in the Design of Cephalosporin Conjugates for Metallo-β-Lactamase Inhibition
- 1UiT The Arctic University of Norway , , ,
- 2University of Copenhagen , , ,
- 3Indian Institute of Technology , , , ,
Abstract
Antibiotic resistance is a major global health challenge, with the rapid spread of metallo-β-lactamase (MBL)-expressing bacteria presenting a serious clinical threat. In this study, we synthesized and investigated a series of novel cephalosporin conjugates envisioned to release MBL inhibitors upon MBL-mediated hydrolysis. The designed compounds consist of a cephalosporin core linked to trifluoromethylated aliphatic thiol-based MBL inhibitors. Conjugates releasing aliphatic thiols upon hydrolysis by the New Delhi Metallo-β-lactamase-1 (NDM-1) were identified, confirming that fluorination improves the leaving group properties of some aliphatic thiols compared to a nonfluorinated control. However, when comparing with a conjugate containing an aromatic thiol, fluorinated aliphatic thiol release appeared slower and mechanistically more complex, thus incompletely resolved. The conjugates exhibited potent inhibitory activity against several subclass B1 MBLs. In addition, the utility of 19F NMR as an alternative method for hydrolysis monitoring was exemplified. The findings highlight the potential, but also some unsolved challenges, of altering the leaving group ability of aliphatic thiol-based inhibitors to exploit the catalytic activity of NDM-1 for the selective release of inhibitors in MBL-producing bacteria.
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BibTeX
@article{kondratieva2026fluorinated,
title = {{Fluorinated Aliphatic Thiols in the Design of Cephalosporin Conjugates for Metallo-β-Lactamase Inhibition}},
author = {Alexandra Kondratieva and Philip Rainsford and Perwez Bakht and Ranjana Pathania and Annette Bayer},
journal = {ACS omega},
year = {2026},
month = sep,
doi = {10.1021/acsomega.6c07917},
url = {https://europepmc.org/article/PMC/PMC13670874},
note = {CC BY},
}
RIS
TY - JOUR
TI - Fluorinated Aliphatic Thiols in the Design of Cephalosporin Conjugates for Metallo-β-Lactamase Inhibition
AU - Alexandra Kondratieva
AU - Philip Rainsford
AU - Perwez Bakht
AU - Ranjana Pathania
AU - Annette Bayer
PY - 2026
DA - 2026/09/30
JO - ACS omega
DO - 10.1021/acsomega.6c07917
UR - https://europepmc.org/article/PMC/PMC13670874
AB - Antibiotic resistance is a major global health challenge, with the rapid spread of metallo-β-lactamase (MBL)-expressing bacteria presenting a serious clinical threat. In this study, we synthesized and investigated a series of novel cephalosporin conjugates envisioned to release MBL inhibitors upon MBL-mediated hydrolysis. The designed compounds consist of a cephalosporin core linked to trifluoromethylated aliphatic thiol-based MBL inhibitors. Conjugates releasing aliphatic thiols upon hydrolysis by the New Delhi Metallo-β-lactamase-1 (NDM-1) were identified, confirming that fluorination improves the leaving group properties of some aliphatic thiols compared to a nonfluorinated control. However, when comparing with a conjugate containing an aromatic thiol, fluorinated aliphatic thiol release appeared slower and mechanistically more complex, thus incompletely resolved. The conjugates exhibited potent inhibitory activity against several subclass B1 MBLs. In addition, the utility of 19F NMR as an alternative method for hydrolysis monitoring was exemplified. The findings highlight the potential, but also some unsolved challenges, of altering the leaving group ability of aliphatic thiol-based inhibitors to exploit the catalytic activity of NDM-1 for the selective release of inhibitors in MBL-producing bacteria.
SN - 2470-1343
ER -