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Cryptic β-Lactamase Evolution Is Driven by Low β-Lactam Concentrations

Permanent lenke
https://hdl.handle.net/10037/21695
DOI
https://doi.org/10.1128/mSphere.00108-21
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article.pdf (2.683Mb)
Publisert versjon (PDF)
Dato
2021-04-28
Type
Journal article
Tidsskriftartikkel
Peer reviewed
Article has an altmetric score of 21
Forfatter
Fröhlich, Christopher; Gama, João Alves; Harms, Klaus; Hirvonen, Viivi H. A.; Lund, Bjarte Aarmo; van der Kamp, Marc W.; Johnsen, Pål Jarle; Samuelsen, Ørjan; Leiros, Hanna-Kirsti S.
Sammendrag
Our current understanding of how low antibiotic concentrations shape the evolution of contemporary β-lactamases is limited. Using the widespread carbapenemase OXA-48, we tested the long-standing hypothesis that selective compartments with low antibiotic concentrations cause standing genetic diversity that could act as a gateway to developing clinical resistance. Here, we subjected Escherichia coli expressing blaOXA-48, on a clinical plasmid, to experimental evolution at sub-MICs of ceftazidime. We identified and characterized seven single variants of OXA-48. Susceptibility profiles and dose-response curves showed that they increased resistance only marginally. However, in competition experiments at sub-MICs of ceftazidime, they demonstrated strong selectable fitness benefits. Increased resistance was also reflected in elevated catalytic efficiencies toward ceftazidime. These changes are likely caused by enhanced flexibility of the Ω- and β5-β6 loops and fine-tuning of preexisting active site residues. In conclusion, low-level concentrations of β-lactams can drive the evolution of β-lactamases through cryptic phenotypes which may act as stepping-stones toward clinical resistance.
Er en del av
Fröhlich, C. (2021). On the Evolvability of OXA-48. A comprehensive study of new functions within the β-lactamase OXA-48. (Doctoral thesis). https://hdl.handle.net/10037/21980.
Forlag
American Society for Microbiology
Sitering
Fröhlich CF, Gama J, Harms K, Hirvonen, Lund BAL, van der Kamp, Johnsen Pj, Samuelsen Ø, Leiros H. Cryptic β-Lactamase Evolution Is Driven by Low β-Lactam Concentrations. mSphere. 2021
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