Escape mutations circumvent a tradeoff between resistance to a beta-lactam and resistance to a beta-lactamase inhibitor

Dor Russ, Fabian Glaser, Einat Shaer Tamar, Idan Yelin, Michael Baym, Eric D. Kelsic, Claudia Zampaloni, Andreas Haldimann and Roy Kishony ()
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Dor Russ: Technion-Israel Institute of Technology
Fabian Glaser: Technion-Israel Institute of Technology
Einat Shaer Tamar: Technion-Israel Institute of Technology
Idan Yelin: Technion-Israel Institute of Technology
Michael Baym: Harvard Medical School
Eric D. Kelsic: Department of Genetics, Harvard Medical School
Claudia Zampaloni: Infectious Diseases, and Ophthalmology, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd
Andreas Haldimann: Infectious Diseases, and Ophthalmology, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd
Roy Kishony: Technion-Israel Institute of Technology

Nature Communications, 2020, vol. 11, issue 1, 1-9

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-020-15666-2

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