TY - JOUR
T1 - Rapid evolution and host immunity drive the rise and fall of carbapenem resistance during an acute Pseudomonas aeruginosa infection
AU - Wheatley, Rachel
AU - Diaz Caballero, Julio
AU - Kapel, Natalia
AU - de Winter, Fien H R
AU - Jangir, Pramod
AU - Quinn, Angus
AU - Del Barrio-Tofiño, Ester
AU - López-Causapé, Carla
AU - Hedge, Jessica
AU - Torrens, Gabriel
AU - Van der Schalk, Thomas
AU - Xavier, Basil Britto
AU - Fernández-Cuenca, Felipe
AU - Arenzana, Angel
AU - Recanatini, Claudia
AU - Timbermont, Leen
AU - Sifakis, Frangiscos
AU - Ruzin, Alexey
AU - Ali, Omar
AU - Lammens, Christine
AU - Goossens, Herman
AU - Kluytmans, Jan
AU - Kumar-Singh, Samir
AU - Oliver, Antonio
AU - Malhotra-Kumar, Surbhi
AU - MacLean, Craig
N1 - 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.
PY - 2021/4/28
Y1 - 2021/4/28
N2 - 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.
AB - 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.
KW - Anti-Bacterial Agents/therapeutic use
KW - Bacterial Outer Membrane Proteins/genetics
KW - Bacterial Proteins/genetics
KW - Drug Resistance, Multiple, Bacterial/genetics
KW - Humans
KW - Hydro-Lyases/genetics
KW - Membrane Transport Proteins/genetics
KW - Meropenem/therapeutic use
KW - Microbial Sensitivity Tests
KW - Middle Aged
KW - Plasmids/genetics
KW - Porins/genetics
KW - Pseudomonas Infections/drug therapy
KW - Pseudomonas aeruginosa/drug effects
KW - Respiratory Tract Infections/diagnosis
KW - Selection, Genetic/genetics
KW - Sequence Analysis, DNA
KW - Shock, Hemorrhagic/microbiology
UR - http://www.scopus.com/inward/record.url?scp=85105076427&partnerID=8YFLogxK
U2 - 10.1038/s41467-021-22814-9
DO - 10.1038/s41467-021-22814-9
M3 - Article
C2 - 33911082
SN - 2041-1723
VL - 12
SP - 1
EP - 12
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 2460
ER -