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Publication Abstract from PubMed

Our current understanding of how low antibiotic concentrations shape the evolution of contemporary beta-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 bla OXA-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 Omega- and beta5-beta6 loops and fine-tuning of preexisting active site residues. In conclusion, low-level concentrations of beta-lactams can drive the evolution of beta-lactamases through cryptic phenotypes which may act as stepping-stones toward clinical resistance.IMPORTANCE Very low antibiotic concentrations have been shown to drive the evolution of antimicrobial resistance. While substantial progress has been made to understand the driving role of low concentrations during resistance development for different antimicrobial classes, the importance of beta-lactams, the most commonly used antibiotics, is still poorly studied. Here, we shed light on the evolutionary impact of low beta-lactam concentrations on the widespread beta-lactamase OXA-48. Our data indicate that the exposure to beta-lactams at very low concentrations enhances beta-lactamase diversity and drives the evolution of beta-lactamases by significantly influencing their substrate specificity. Thus, in contrast to high concentrations, low levels of these drugs may substantially contribute to the diversification and divergent evolution of these enzymes, providing a standing genetic diversity that can be selected and mobilized when antibiotic pressure increases.

Cryptic beta-Lactamase Evolution Is Driven by Low beta-Lactam Concentrations.,Frohlich C, Gama JA, Harms K, Hirvonen VHA, Lund BA, van der Kamp MW, Johnsen PJ, Samuelsen O, Leiros HS mSphere. 2021 Apr 28;6(2). pii: 6/2/e00108-21. doi: 10.1128/mSphere.00108-21. PMID:33910990^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.