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Compensatory mutations modulate the competitiveness and dynamics of plasmid-mediated colistin resistance in Escherichia coli clones

Yang, Qiu E., MacLean, Craig, Papkou, Andrei, Pritchard, Manon, Powell, Lydia, Thomas, David, Andrey, Diego O., Li, Mei, Spiller, Brad, Yang, Wang and Walsh, Timothy R. 2020. Compensatory mutations modulate the competitiveness and dynamics of plasmid-mediated colistin resistance in Escherichia coli clones. ISME Journal 10.1038/s41396-019-0578-6

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Abstract

The emergence of mobile colistin resistance (mcr) threatens to undermine the clinical efficacy of the last antibiotic that can be used to treat serious infections caused by Gram-negative pathogens. Here we measure the fitness cost of a newly discovered MCR-3 using in vitro growth and competition assays. mcr-3 expression confers a lower fitness cost than mcr-1, as determined by competitive ability and cell viability. Consistent with these findings, plasmids carrying mcr-3 have higher stability than mcr-1 plasmids across a range of Escherichia coli strains. Crucially, mcr-3 plasmids can stably persist, even in the absence of colistin. Recent compensatory evolution has helped to offset the cost of mcr-3 expression, as demonstrated by the high fitness of mcr-3.5 as opposed to mcr-3.1. Reconstructing all of the possible evolutionary trajectories from mcr-3.1 to mcr-3.5 reveals a complex fitness landscape shaped by negative epistasis between compensatory and neutral mutations. Our findings highlight the importance of fitness costs and compensatory evolution in driving the dynamics and stability of mobile colistin resistance in bacterial populations, and they highlight the need to understand how processes (other than colistin use) impact mcr dynamics.

Item Type: Article
Date Type: Published Online
Status: In Press
Schools: Dentistry
Medicine
Publisher: Springer Nature
ISSN: 1751-7362
Funders: MRC
Date of First Compliant Deposit: 9 January 2020
Date of Acceptance: 17 December 2019
Last Modified: 21 Jan 2020 13:13
URI: http://orca-mwe.cf.ac.uk/id/eprint/128379

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