Rapid evolution and host immunity drive the rise and fall of carbapenem resistance during an acute Pseudomonas aeruginosa infection
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Published:2021-04-28
Issue:1
Volume:12
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Wheatley RachelORCID, Diaz Caballero Julio, Kapel Natalia, de Winter Fien H. R.ORCID, Jangir Pramod, Quinn AngusORCID, del Barrio-Tofiño Ester, López-Causapé Carla, Hedge JessicaORCID, Torrens Gabriel, Van der Schalk ThomasORCID, Xavier Basil BrittoORCID, Fernández-Cuenca Felipe, Arenzana Angel, Recanatini ClaudiaORCID, Timbermont LeenORCID, Sifakis Frangiscos, Ruzin Alexey, Ali Omar, Lammens Christine, Goossens Herman, Kluytmans Jan, Kumar-Singh Samir, Oliver Antonio, Malhotra-Kumar SurbhiORCID, MacLean CraigORCID
Abstract
AbstractIt is well established that antibiotic treatment selects for resistance, but the dynamics of this process during infections are poorly understood. Here we map the responses of Pseudomonas aeruginosa to treatment in high definition during a lung infection of a single ICU patient. Host immunity and antibiotic therapy with meropenem suppressed P. aeruginosa, but a second wave of infection emerged due to the growth of oprD and wbpM meropenem resistant mutants that evolved in situ. Selection then led to a loss of resistance by decreasing the prevalence of low fitness oprD mutants, increasing the frequency of high fitness mutants lacking the MexAB-OprM efflux pump, and decreasing the copy number of a multidrug resistance plasmid. Ultimately, host immunity suppressed wbpM mutants with high meropenem resistance and fitness. Our study highlights how natural selection and host immunity interact to drive both the rapid rise, and fall, of resistance during infection.
Funder
Wellcome Trust Innovative Medicines Initiative
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry
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