Document Type
Article
Publication Date
6-2022
Publisher
Nature Publishing Group (Macmillan Publishers Limited)
Source Publication
Nature Microbiology
Source ISSN
2058-5276
Original Item ID
10.1101/2021.04.07.438861
Abstract
Acinetobacter baumannii is increasingly refractory to antibiotic treatment in healthcare settings. As is true of most human pathogens, the genetic path to antimicrobial resistance (AMR) and the role that the immune system plays in modulating AMR during disease are poorly understood. Here we reproduced several routes to fluoroquinolone resistance, performing evolution experiments using sequential lung infections in mice that are replete or depleted of neutrophils, providing two key insights into the evolution of drug resistance. First, neutropenic hosts acted as reservoirs for the accumulation of drug resistance during drug treatment. Selection for variants with altered drug sensitivity profiles arose readily in the absence of neutrophils, while immunocompetent animals restricted the appearance of these variants. Secondly, antibiotic treatment failure in the immunocompromised host was shown to occur without clinically defined resistance, an unexpected result that provides a model for how antibiotic failure occurs clinically in the absence of AMR. The genetic mechanism underlying both these results is initiated by mutations activating the drug egress pump regulator AdeL, which drives persistence in the presence of antibiotic. Therefore, antibiotic persistence mutations present a two-pronged risk during disease, causing drug treatment failure in the immunocompromised host while simultaneously increasing the emergence of high-level AMR.
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.
Recommended Citation
Huo, Wenwen; Busch, Lindsay M.; Hernandez-Bird, Juan; Hamami, Efrat; Marshall, Christopher; Geisinger, Edward; Cooper, Vaughn S.; van Opijnen, Tim; Rosch, Jason W.; and Isberg, Ralph R., "Immunosuppression Broadens Evolutionary Pathways to Treatment Failure during Acinetobacter baumannii Pneumonia" (2022). Biological Sciences Faculty Research and Publications. 925.
https://epublications.marquette.edu/bio_fac/925
Comments
Accepted version. Nature Microbiology, Vol. 7 (June 2022): 796-809. DOI. © 2022 Nature Publishing Group (Macmillan Publisher Limited). Used with permission.