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TEM- and SHV-derived extended-spectrum beta-lactamases: relationship between selection, structure and function
S K Du Bois1, M S Marriott, S G Amyes
1Department of Medical Microbiology, Medical School, University of Edinburgh, UK.
The Journal of Antimicrobial Chemotherapy
|January 1, 1995
Summary
Later-generation cephalosporins faced rapid resistance due to mutations in TEM and SHV beta-lactamase genes. These genetic changes enhanced enzyme activity, enabling hydrolysis of newer antibiotics.
Area of Science:
- Microbiology
- Molecular Biology
- Biochemistry
Background:
- Earlier beta-lactam antibiotics faced resistance mediated by beta-lactamase enzymes.
- Later-generation cephalosporins were designed to circumvent this resistance.
Purpose of the Study:
- To investigate the molecular mechanisms by which beta-lactamase enzymes evolved resistance to newer cephalosporins.
- To understand the role of specific mutations in conferring enhanced hydrolytic activity.
Main Methods:
- Analysis of plasmid-encoded TEM and SHV beta-lactamase genes.
- Identification of point mutations affecting amino acids at the enzyme's active site.
- Correlation of structural changes with altered enzymatic activity and drug resistance.
Main Results:
- Plasmid-borne TEM and SHV beta-lactamase genes rapidly acquired point mutations post-cephalosporin introduction.
- Mutations altered active site amino acids, enabling hydrolysis of later-generation cephalosporins.
- Successive mutations cumulatively increased resistance, with altered functions linked to structural changes.
Conclusions:
- Beta-lactamase evolution is a rapid process driven by selective pressure from new antibiotics.
- Specific amino acid substitutions in beta-lactamases are critical for overcoming cephalosporin efficacy.
- Understanding these evolutionary dynamics is key to developing future antimicrobial strategies.