Rapid evolution and host immunity drive the rise and fall of carbapenem resistance during an acute Pseudomonas aeruginosa infection
Publication date
2021-04-28
Authors
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
Editors
Advisors
Supervisors
Document Type
Article
Metadata
Show full item recordCollections
License
cc_by
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 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.
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
Citation
Wheatley, R, Diaz Caballero, J, Kapel, N, de Winter, F H R, Jangir, P, Quinn, A, Del Barrio-Tofiño, E, López-Causapé, C, Hedge, J, Torrens, G, Van der Schalk, T, Xavier, B B, Fernández-Cuenca, F, Arenzana, A, Recanatini, C, Timbermont, L, Sifakis, F, Ruzin, A, Ali, O, Lammens, C, Goossens, H, Kluytmans, J, Kumar-Singh, S, Oliver, A, Malhotra-Kumar, S & MacLean, C 2021, 'Rapid evolution and host immunity drive the rise and fall of carbapenem resistance during an acute Pseudomonas aeruginosa infection', Nature Communications, vol. 12, no. 1, 2460, pp. 1-12. https://doi.org/10.1038/s41467-021-22814-9