质粒
抗生素耐药性
生物
水平基因转移
细菌
抗生素
实验进化
遗传学
微生物学
基因
基因组
作者
Javier DelaFuente,Laura Toribio-Celestino,Alfonso Santos-López,Ricardo León‐Sampedro,Aída Alonso-del Valle,Coloma Costas,Marta Hernández-García,Lun Cui,Jerónimo Rodríguez-Beltrán,David Bikard,Rafael Cantón,Álvaro San Millán
标识
DOI:10.1101/2022.05.31.493991
摘要
Abstract Antibiotic resistance (AMR) in bacteria is a major threat to public health, and one of the key elements in the spread and evolution of AMR in clinical pathogens is the transfer of conjugative plasmids. The drivers of AMR evolution have been extensively studied in vitro , but the evolution of plasmid-mediated AMR in vivo remains poorly explored. Here, we tracked the evolution of the clinically-relevant plasmid pOXA-48, which confers resistance to the last-resort antibiotics carbapenems, in a large collection of enterobacterial clones isolated from the gut of hospitalised patients. Combining genomic and experimental approaches, we first characterized plasmid diversity and the genotypic and phenotypic effects of multiple plasmid mutations on a common genetic background. Second, using cutting-edge genomic editing in wild-type multidrug resistant enterobacteria, we dissected three cases of within-patient plasmid-mediated AMR evolution. Our results revealed, for the first time, compensatory evolution of plasmid-associated fitness cost, as well as the evolution of enhanced plasmid-mediated AMR, in bacteria evolving within the gut of hospitalised patients. Crucially, we observed that the evolution of plasmid-mediated AMR in vivo involves a pivotal trade-off between resistance levels and bacterial fitness. This study highlights the need to develop new evolution-informed approaches to tackle plasmid-mediated AMR dissemination.
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