Cryptic β-Lactamase Evolution Is Driven by Low β-Lactam Concentrations
Christopher Fröhlich, João Alves Gama, Klaus Harms, Viivi H. A. Hirvonen, Bjarte Aarmo Lund, Marc W. van der Kamp, Pål J. Johnsen, Ørjan Samuelsen, Hanna‐Kirsti S. Leiros
Abstract
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 β-lactams, the most commonly used antibiotics, is still poorly studied. Here, we shed light on the evolutionary impact of low β-lactam concentrations on the widespread β-lactamase OXA-48. Our data indicate that the exposure to β-lactams at very low concentrations enhances β-lactamase diversity and drives the evolution of β-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.