7ASS

OXA-48_L67F_CAZ. What Doesnt Kill You Makes You Stronger: Sub-MIC Selection Drives Cryptic Evolution of OXA-48

7ASS の概要

• エントリーDOI: 10.2210/pdb7ass/pdb
• 分子名称: Beta-lactamase, CHLORIDE ION, hydrolyzed ceftazidime, ... (4 entities in total)
• 機能のキーワード: oxa-48, ceftazidime, resistance development, cryptic evolution, escherichia coli, carbapenemase, carbapenem, collateral sensitivity, sub-mic, antibiotic
• 由来する生物種: Klebsiella pneumoniae
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 123203.42

構造登録者

Frohlich, C.,Leiros, H.-K.S. (登録日: 2020-10-28, 公開日: 2020-12-16, 最終更新日: 2024-01-31)

主引用文献

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.S.
Cryptic beta-Lactamase Evolution Is Driven by Low beta-Lactam Concentrations.
Msphere, 6:-, 2021

PubMed Abstract: 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 expressing , 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. 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.

PubMed: 33910990
DOI: 10.1128/mSphere.00108-21

実験手法

X-RAY DIFFRACTION (1.91 Å)