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Rapid evolution drives the rise and fall of carbapenem resistance during an acute Pseudomonas aeruginosa infection

Rachel Wheatley, Julio Diaz Caballero, Natalia Kapel, Angus Quinn, Ester del Barrio-Tofiño, Carla López-Causapé, Jessica Hedge, Gabriel Torrens, Thomas Van der Schalk, Basil Britto Xavier, Felipe Fernández-Cuenca, Angel Arenzana, Claudia Recanatini, Leen Timbermont, Frangiscos Sifakis, Alexey Ruzin, Omar Ali, Christine Lammens, Herman Goossens, Jan Kluytmans, Samir Kumar-Singh, Antonio Oliver, Surbhi Malhotra-Kumar, Craig MacLean
doi: https://doi.org/10.1101/2020.08.10.243741
Rachel Wheatley
1University of Oxford, Department of Zoology, Oxford OX1 3SZ, UK
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Julio Diaz Caballero
1University of Oxford, Department of Zoology, Oxford OX1 3SZ, UK
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Natalia Kapel
1University of Oxford, Department of Zoology, Oxford OX1 3SZ, UK
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Angus Quinn
1University of Oxford, Department of Zoology, Oxford OX1 3SZ, UK
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Ester del Barrio-Tofiño
2Hospital Universitario Son Espases, Palma de Mallorca, Spain
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Carla López-Causapé
2Hospital Universitario Son Espases, Palma de Mallorca, Spain
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Jessica Hedge
1University of Oxford, Department of Zoology, Oxford OX1 3SZ, UK
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Gabriel Torrens
2Hospital Universitario Son Espases, Palma de Mallorca, Spain
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Thomas Van der Schalk
3Laboratory of Medical Microbiology, Vaccine and Infectious Disease Institute, University of Antwerp, Universiteitsplein 1, B-2610 Wilrijk, Belgium
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Basil Britto Xavier
3Laboratory of Medical Microbiology, Vaccine and Infectious Disease Institute, University of Antwerp, Universiteitsplein 1, B-2610 Wilrijk, Belgium
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Felipe Fernández-Cuenca
4Departamento de Medicina, Universidad de Sevilla, Seville, Spain
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Angel Arenzana
4Departamento de Medicina, Universidad de Sevilla, Seville, Spain
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Claudia Recanatini
5Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
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Leen Timbermont
3Laboratory of Medical Microbiology, Vaccine and Infectious Disease Institute, University of Antwerp, Universiteitsplein 1, B-2610 Wilrijk, Belgium
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Frangiscos Sifakis
6Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, Connecticut, USA
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Alexey Ruzin
7Microbial Sciences, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland, USA
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Omar Ali
8Viela Bio, Gaithersburg, Maryland, USA
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Christine Lammens
3Laboratory of Medical Microbiology, Vaccine and Infectious Disease Institute, University of Antwerp, Universiteitsplein 1, B-2610 Wilrijk, Belgium
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Herman Goossens
3Laboratory of Medical Microbiology, Vaccine and Infectious Disease Institute, University of Antwerp, Universiteitsplein 1, B-2610 Wilrijk, Belgium
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Jan Kluytmans
5Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
9Microvida Laboratory for Medical Microbiology and Department of Infection Control, Amphia Hospital, Breda, Netherlands
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Samir Kumar-Singh
3Laboratory of Medical Microbiology, Vaccine and Infectious Disease Institute, University of Antwerp, Universiteitsplein 1, B-2610 Wilrijk, Belgium
10Molecular Pathology Group, Faculty of Medicine–Laboratory of Cell Biology and Histology, University of Antwerp, Universiteitsplein 1, B-2610 Wilrijk, Belgium
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Antonio Oliver
2Hospital Universitario Son Espases, Palma de Mallorca, Spain
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Surbhi Malhotra-Kumar
3Laboratory of Medical Microbiology, Vaccine and Infectious Disease Institute, University of Antwerp, Universiteitsplein 1, B-2610 Wilrijk, Belgium
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Craig MacLean
1University of Oxford, Department of Zoology, Oxford OX1 3SZ, UK
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  • For correspondence: craig.maclean@zoo.ox.ac.uk
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Abstract

It is well established that antibiotic treatment selects for resistance in pathogenic bacteria. However, the evolutionary responses of pathogen populations to antibiotic treatment during infections remain poorly resolved, especially in acute infections. Here we map the evolutionary responses to treatment in high definition through genomic and phenotypic characterization of >100 isolates from a patient with P. aeruginosa pneumonia. Antibiotic therapy (meropenem, colistin) caused a rapid crash of the P. aeruginosa population in the lung, but this decline was followed by the spread of meropenem resistance mutations that restrict antibiotic uptake (oprD) or modify LPS biosynthesis (wbpM). Low fitness strains with high-level meropenem resistance (oprD) were then replaced by high fitness strains with ‘anti-resistance’ mutations in the MexAB-OprM efflux pump, causing a rapid decline in resistance to both meropenem and a collateral loss of resistance to a broad spectrum of antibiotics. In contrast, we did not observe any evolutionary responses to antibiotic treatment in the intestinal population of P. aeruginosa. Carbapenem antibiotics are key to the treatment of infections caused by Gram negative pathogens, and our work highlights the ability of natural selection to drive both the rapid rise and fall of carbapenem resistance during acute infections.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Rapid evolution drives the rise and fall of carbapenem resistance during an acute Pseudomonas aeruginosa infection
Rachel Wheatley, Julio Diaz Caballero, Natalia Kapel, Angus Quinn, Ester del Barrio-Tofiño, Carla López-Causapé, Jessica Hedge, Gabriel Torrens, Thomas Van der Schalk, Basil Britto Xavier, Felipe Fernández-Cuenca, Angel Arenzana, Claudia Recanatini, Leen Timbermont, Frangiscos Sifakis, Alexey Ruzin, Omar Ali, Christine Lammens, Herman Goossens, Jan Kluytmans, Samir Kumar-Singh, Antonio Oliver, Surbhi Malhotra-Kumar, Craig MacLean
bioRxiv 2020.08.10.243741; doi: https://doi.org/10.1101/2020.08.10.243741
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Rapid evolution drives the rise and fall of carbapenem resistance during an acute Pseudomonas aeruginosa infection
Rachel Wheatley, Julio Diaz Caballero, Natalia Kapel, Angus Quinn, Ester del Barrio-Tofiño, Carla López-Causapé, Jessica Hedge, Gabriel Torrens, Thomas Van der Schalk, Basil Britto Xavier, Felipe Fernández-Cuenca, Angel Arenzana, Claudia Recanatini, Leen Timbermont, Frangiscos Sifakis, Alexey Ruzin, Omar Ali, Christine Lammens, Herman Goossens, Jan Kluytmans, Samir Kumar-Singh, Antonio Oliver, Surbhi Malhotra-Kumar, Craig MacLean
bioRxiv 2020.08.10.243741; doi: https://doi.org/10.1101/2020.08.10.243741

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