Escape mutations circumvent a tradeoff between resistance to a beta-lactam and resistance to a beta-lactamase inhibitor
| Autor: | Michael H. Baym, Claudia Zampaloni, Roy Kishony, Andreas Haldimann, Fabian Glaser, Idan Yelin, Dor Russ, Eric D. Kelsic, Einat Shaer Tamar |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Avibactam Science 030106 microbiology Mutant General Physics and Astronomy Drug resistance Microbial Sensitivity Tests medicine.disease_cause beta-Lactams Antimicrobial resistance General Biochemistry Genetics and Molecular Biology beta-Lactamases Article Bacterial genetics Evolution Molecular Bacterial evolution 03 medical and health sciences chemistry.chemical_compound Inhibitory Concentration 50 Antibiotic resistance Bacterial Proteins Drug Resistance Multiple Bacterial medicine Escherichia coli lcsh:Science Genetics Mutation Multidisciplinary Binding Sites biology Wild type General Chemistry Anti-Bacterial Agents Molecular Docking Simulation 030104 developmental biology chemistry Amino Acid Substitution Experimental evolution Enzyme inhibitor biology.protein lcsh:Q Evolvability beta-Lactamase Inhibitors Azabicyclo Compounds |
| Zdroj: | Nature Communications, Vol 11, Iss 1, Pp 1-9 (2020) Nature Communications |
| ISSN: | 2041-1723 |
| Popis: | Beta-lactamase inhibitors are increasingly used to counteract antibiotic resistance mediated by beta-lactamase enzymes. These inhibitors compete with the beta-lactam antibiotic for the same binding site on the beta-lactamase, thus generating an evolutionary tradeoff: mutations that increase the enzyme’s beta-lactamase activity tend to increase also its susceptibility to the inhibitor. Here, we investigate how common and accessible are mutants that escape this adaptive tradeoff. Screening a deep mutant library of the blaampC beta-lactamase gene of Escherichia coli, we identified mutations that allow growth at beta-lactam concentrations far exceeding those inhibiting growth of the wildtype strain, even in the presence of the enzyme inhibitor (avibactam). These escape mutations are rare and drug-specific, and some combinations of avibactam with beta-lactam drugs appear to prevent such escape phenotypes. Our results, showing differential adaptive potential of blaampC to combinations of avibactam and different beta-lactam antibiotics, suggest that it may be possible to identify treatments that are more resilient to evolution of resistance. Beta-lactam antibiotics and beta-lactamase inhibitors compete for the same binding site on beta-lactamases; thus, mutations that increase beta-lactamase activity likely increase also susceptibility to the inhibitor. Here, Russ et al. identify rare mutations in the ampC beta-lactamase gene that escape this adaptive tradeoff specifically for certain drug combinations. |
| Databáze: | OpenAIRE |
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