000			02871 am a22003373u 4500
042			_adc
100	1	0	_aDelaFuente, Javier _eauthor _91690
700	1	0	_aToribio-Celestino, Laura _eauthor _91691
700	1	0	_aSantos-Lopez, Alfonso _eauthor _91692
700	1	0	_aLeón-Sampedro, Ricardo _eauthor _91693
700	1	0	_aValle, Aida Alonso-del _eauthor _91694
700	1	0	_aCostas, Coloma _eauthor _91695
700	1	0	_aHernández-García, Marta _eauthor _91696
700	1	0	_aCui, Lun _eauthor _91697
700	1	0	_aRodríguez-Beltrán, Jerónimo _eauthor _91698
700	1	0	_aBikard, David _eauthor _91699
700	1	0	_aCantón, Rafael _eauthor _91700
700	1	0	_aMillan, Alvaro San _eauthor _91701
245	0	0	_aWithin-patient evolution of plasmid-mediated antimicrobial resistance
260			_c2022-10-27.
500			_a/pmc/articles/PMC7613874/
500			_a/pubmed/36303001
520			_aAntimicrobial 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 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 pOXA-48-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.
540			_a
540			_ahttps://www.springernature.com/gp/open-research/policies/accepted-manuscript-termsUsers may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: https://www.springernature.com/gp/open-research/policies/accepted-manuscript-terms
546			_aen
690			_aArticle
655	7		_aText _2local
786	0		_nNat Ecol Evol
856	4	1	_uhttp://dx.doi.org/10.1038/s41559-022-01908-7 _zConnect to this object online.
999			_c1745 _d1745