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Off-Target Integron Activity Leads to Rapid Plasmid Compensatory Evolution in Response to Antibiotic Selection Pressure

Investigación publicada en mBio

22 de febrero de 2023

Integrons are mobile genetic elements that have played an important role in the dissemination of antibiotic resistance. Under stress, the integron can generate combinatorial variation in resistance cassette expression by cassette reshuffling, accelerating the evolution of resistance. However, the flexibility of the integron integrase site recognition motif hints at potential off-target effects of the integrase on the rest of the genome that may have important evolutionary consequences. Here, we test this hypothesis by selecting for increased-piperacillin-resistance populations of Pseudomonas aeruginosa with a mobile integron containing a difficult-to-mobilize β-lactamase cassette to minimize the potential for adaptive cassette reshuffling. We found that integron activity can decrease the overall survival rate but also improve the fitness of the surviving populations. Off-target inversions mediated by the integron accelerated plasmid adaptation by disrupting costly conjugative genes otherwise mutated in control populations lacking a functional integrase. Plasmids containing integron-mediated inversions were associated with lower plasmid costs and higher stability than plasmids carrying mutations albeit at the cost of a reduced conjugative ability. These findings highlight the potential for integrons to create structural variation that can drive bacterial evolution, and they provide an interesting example showing how antibiotic pressure can drive the loss of conjugative genes. IMPORTANCE Tackling the public health challenge created by antibiotic resistance requires understanding the mechanisms driving its evolution. Mobile integrons are widespread genetic platforms heavily involved in the spread of antibiotic resistance. Through the action of the integrase enzyme, integrons allow bacteria to capture, excise, and shuffle antibiotic resistance gene cassettes. This integrase enzyme is characterized by its ability to recognize a wide range of recombination sites, which allows it to easily capture diverse resistance cassettes but which may also lead to off-target reactions with the rest of the genome. Using experimental evolution, we tested the off-target impact of integron activity. We found that integrons increased the fitness of the surviving bacteria through extensive genomic rearrangements of the plasmids carrying the integrons, reducing their ability to spread horizontally. These results show that integrons not only accelerate resistance evolution but also can generate extensive structural variation, driving bacterial evolution beyond antibiotic resistance




Souque C., Escudero JA. y MacLean RC.




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Off-Target Integron Activity Leads to Rapid Plasmid Compensatory Evolution in Response to Antibiotic Selection Pressure

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Off-Target Integron Activity Leads to Rapid Plasmid Compensatory Evolution in Response to Antibiotic Selection Pressure



Participantes:

University of OxfordDepartment of Zoology. University of Oxford.

Department of Biomedical Informatics and Laboratory of Systems Pharmacology. Harvard Medical School (HMS).

Universidad ComplutenseServicio de Zoonosis de Transmisión Alimentaria y Resistencia a Antimicrobianos (ZTA). Centro de Vigilancia Sanitaria Veterinaria (VISAVET). Universidad Complutense (UCM).

Universidad ComplutenseDepartamento de Sanidad Animal. Facultad de Veterinaria. Universidad Complutense (UCM).







mBio
FACTOR YEAR Q
5.100 2023

NLMID: 101519231

PMID: 36840554

ISSN: 2150-7511



TÍTULO: Off-Target Integron Activity Leads to Rapid Plasmid Compensatory Evolution in Response to Antibiotic Selection Pressure


REVISTA: mBio


NUMERACIÓN: e0253722


AÑO: 2023


EDITORIAL: American Society for Microbiology


AUTORES: Souque C., Escudero JA. and MacLean RC.


José Antonio Escudero García-Calderón

DOI: https://doi.org/10.1128/mbio.02537-22


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