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dc.contributor.authorFröhlich, Christopher
dc.contributor.authorGama, João Alves
dc.contributor.authorHarms, Klaus
dc.contributor.authorHirvonen, Viivi H. A.
dc.contributor.authorLund, Bjarte Aarmo
dc.contributor.authorvan der Kamp, Marc W.
dc.contributor.authorJohnsen, Pål Jarle
dc.contributor.authorSamuelsen, Ørjan
dc.contributor.authorLeiros, Hanna-Kirsti S.
dc.date.accessioned2021-07-02T09:51:28Z
dc.date.available2021-07-02T09:51:28Z
dc.date.issued2021-04-28
dc.description.abstractOur 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 <i>Escherichia coli</i> expressing bla<sub>OXA-48</sub>, 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.en_US
dc.identifier.citationFröhlich 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. 2021en_US
dc.identifier.cristinIDFRIDAID 1907334
dc.identifier.doi10.1128/mSphere.00108-21
dc.identifier.issn2379-5042
dc.identifier.urihttps://hdl.handle.net/10037/21695
dc.language.isoengen_US
dc.publisherAmerican Society for Microbiologyen_US
dc.relation.ispartofFröhlich, C. (2021). On the Evolvability of OXA-48. A comprehensive study of new functions within the β-lactamase OXA-48. (Doctoral thesis). <a href=https://hdl.handle.net/10037/21980>https://hdl.handle.net/10037/21980</a>.
dc.relation.journalmSphere
dc.relation.projectIDinfo:eu-repo/grantAgreement/RCN/BEDREHELSE/273332/Norway/Inhibition of clinically relevant carbapenemases/ICARBA/en_US
dc.relation.projectIDinfo:eu-repo/grantAgreement/RCN/SFF/262695/Norway/Hylleraas Centre for Quantum Molecular Sciences//en_US
dc.relation.projectIDinfo:eu-repo/grantAgreement/RCN/FRINATEK/274858/Norway/Evolutionary Principles of Biocatalysts From Extreme Environments//en_US
dc.rights.accessRightsopenAccessen_US
dc.rights.holderCopyright 2021 The Author(s)en_US
dc.subjectVDP::Medical disciplines: 700::Basic medical, dental and veterinary science disciplines: 710::Medical microbiology: 715en_US
dc.subjectVDP::Medisinske Fag: 700::Basale medisinske, odontologiske og veterinærmedisinske fag: 710::Medisinsk mikrobiologi: 715en_US
dc.titleCryptic β-Lactamase Evolution Is Driven by Low β-Lactam Concentrationsen_US
dc.type.versionpublishedVersionen_US
dc.typeJournal articleen_US
dc.typeTidsskriftartikkelen_US
dc.typePeer revieweden_US


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