Rapid evolution and host immunity drive the rise and fall of carbapenem resistance during an acute Pseudomonas aeruginosa infection
Wheatley, Rachel; Diaz Caballero, Julio; Kapel, Natalia; de Winter, Fien H R; Jangir, Pramod; Quinn, Angus; Del Barrio-Tofiño, Ester; López-Causapé, Carla; Hedge, Jessica; Torrens, Gabriel; Van der Schalk, Thomas; Xavier, Basil Britto; Fernández-Cuenca, Felipe; Arenzana, Angel; Recanatini, Claudia; Timbermont, Leen; Sifakis, Frangiscos; Ruzin, Alexey; Ali, Omar; Lammens, Christine; Goossens, Herman; Kluytmans, Jan; Kumar-Singh, Samir; Oliver, Antonio; Malhotra-Kumar, Surbhi; MacLean, Craig
(2021) Nature Communications, volume 12, issue 1, pp. 1 - 12
(Article)
Abstract
It 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
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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.
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Keywords: Anti-Bacterial Agents/therapeutic use, Bacterial Outer Membrane Proteins/genetics, Bacterial Proteins/genetics, Drug Resistance, Multiple, Bacterial/genetics, Humans, Hydro-Lyases/genetics, Membrane Transport Proteins/genetics, Meropenem/therapeutic use, Microbial Sensitivity Tests, Middle Aged, Plasmids/genetics, Porins/genetics, Pseudomonas Infections/drug therapy, Pseudomonas aeruginosa/drug effects, Respiratory Tract Infections/diagnosis, Selection, Genetic/genetics, Sequence Analysis, DNA, Shock, Hemorrhagic/microbiology, General Physics and Astronomy, General Chemistry, General Biochemistry,Genetics and Molecular Biology, Research Support, Non-U.S. Gov't, Journal Article
ISSN: 2041-1723
Publisher: Nature Publishing Group
Note: Funding Information: This research was supported by Wellcome Trust Grant (106918/Z/15/Z) and the Innovative Medicines Initiative Joint Undertaking under COMBACTE-MAGNET (Combatting Bacterial Resistance in Europe-Molecules against Gram-negative Infections, grant agreement no. 115737) and COMBACTE-NET (Combatting Bacterial Resistance in Europe-Networks, grant agreement no. 115523), resources of which are composed of financial contribution from the European Union’s Seventh Framework Program (FP7/ 2007-2013) and EFPIA companies’ in kind contribution. We thank the Oxford Genomics Center (funded by Wellcome Trust Grant 203141/Z/16/Z) for the generation and initial processing of Illumina sequence data. Publisher Copyright: © 2021, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.
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