期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 40, 期 -, 页码 -出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2021.116183
关键词
Antibiotic resistance; Metallo-β -lactamase; IMP-1; MBL inhibitors; Native state mass spectrometry
资金
- National Institutes of Health [GM134454, GM128595]
- National Institute of Allergy and Infectious Diseases of the National Institutes of Health [R01-GM111926, R01-AI149444]
The study demonstrates similar inhibitory mechanisms of different metallo beta-lactamase inhibitors towards different metallo beta-lactamases.
In an effort to probe the biophysical mechanisms of inhibition for ten previously-reported inhibitors of metallo beta-lactamases (MBL) with MBL IMP-1, equilibrium dialysis, metal analyses coupled with atomic absorption spectroscopy (AAS), native state mass spectrometry (native MS), and ultraviolet-visible spectrophotometry (UVVIS) were used. 6-(1H-tetrazol-5-yl) picolinic acid (1T5PA), ANT431, D/L-captopril, thiorphan, and tiopronin were shown to form IMP-1/Zn(II)/inhibitor ternary complexes, while dipicolinic acid (DPA) and 4-(3-aminophenyl)pyridine-2,6-dicarboxylic acid (3AP-DPA) stripped some metal from the active site of IMP but also formed ternary complexes. DPA and 3AP-DPA stripped less metal from IMP-1 than from VIM-2 but stripped more metal from IMP-1 than from NDM-1. In contrast to a previous report, pterostilbene does not appear to bind to IMP-1 under our conditions. These results, along with previous studies, demonstrate similar mechanisms of inhibition toward different MBLs for different MBL inhibitors.
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