Cryptic β-lactamase evolution is driven by low β-lactam concentrations

Frohlich, C.; Gama, J. A.; Harms, K.; Hirvonen, V. H. A.; Lund, B. A.; van der Kamp, M. W.; Johnsen, P. J.; Samuelsen, O.; Leiros, H.-K. S.

doi:10.1101/2020.12.01.404343

bioRxiv · 10.1101/2020.12.01.404343

Cryptic β-lactamase evolution is driven by low β-lactam concentrations

Frohlich, C.·Gama, J. A.·Harms, K.·Hirvonen, V. H. A.·Lund, B. A.·van der Kamp, M. W.·Johnsen, P. J.·Samuelsen, O.·Leiros, H.-K. S.

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Abstract

Our current understanding of how low antibiotic concentrations shape the evolution of contemporary {beta}-lactamases is limited. Using the wide-spread 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 develop clinical resistance. Here, we subjected Escherichia coli expressing blaOXA-48, on a clinical plasmid, to experimental evolution at sub-minimum inhibitory concentrations (sub-MIC) 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-MIC of ceftazidime, they showed strong selectable fitness benefits. Increased resistance was also reflected in elevated catalytic efficiencies towards ceftazidime. These changes are likely caused by enhanced flexibility of the {Omega}- and {beta}5-{beta}6 loops. In conclusion, low-level concentrations of {beta}-lactams can drive the evolution of {beta}-lactamases through cryptic phenotypes which may act as stepping-stones towards clinical resistance.

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Frohlich, C., Gama, J. A., Harms, K., Hirvonen, V. H. A., Lund, B. A., van der Kamp, M. W., Johnsen, P. J., Samuelsen, O., Leiros, H.-K. S.. 2020-12-02. Cryptic β-lactamase evolution is driven by low β-lactam concentrations. https://doi.org/10.1101/2020.12.01.404343

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