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Challenges in the Development of a Thiol-Based Broad-Spectrum Inhibitor for Metallo-β-Lactamases
- Source :
- ACS Infectious Diseases. 4:360-372
- Publication Year :
- 2017
- Publisher :
- American Chemical Society (ACS), 2017.
-
Abstract
- Pathogens, expressing metallo-β-lactamases (MBLs), become resistant against most β-lactam antibiotics. Besides the dragging search for new antibiotics, development of MBL inhibitors would be an alternative weapon against resistant bacterial pathogens. Inhibition of resistance enzymes could restore the antibacterial activity of β-lactams. Various approaches to MBL inhibitors are described; among others, the promising motif of a zinc coordinating thiol moiety is very popular. Nevertheless, since the first report of a thiol-based MBL inhibitor (thiomandelic acid) in 2001, no steps in development of thiol based MBL inhibitors were reported that go beyond clinical isolate testing. In this study, we report on the synthesis and biochemical characterization of thiol-based MBL inhibitors and highlight the challenges behind the development of thiol-based compounds, which exhibit good in vitro activity toward a broad spectrum of MBLs, selectivity against human off-targets, and reasonable activity against clinical isolates.
- Subjects :
- 0301 basic medicine
chemistry.chemical_classification
medicine.drug_class
Antibiotics
chemical and pharmacologic phenomena
Biology
bacterial infections and mycoses
beta-Lactam Resistance
In vitro
03 medical and health sciences
030104 developmental biology
Infectious Diseases
Enzyme
Antibiotic resistance
chemistry
Biochemistry
Drug Discovery
Hydrolase
Thiol
medicine
Moiety
Sulfhydryl Compounds
beta-Lactamase Inhibitors
Antibacterial activity
Subjects
Details
- ISSN :
- 23738227
- Volume :
- 4
- Database :
- OpenAIRE
- Journal :
- ACS Infectious Diseases
- Accession number :
- edsair.doi.dedup.....b9de5e8d4b7097a7a3ca2b01004426c5