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Inhibitory concentrations of ciprofloxacin induce an adaptive response promoting the intracellular survival of Salmonella Typhimurium

Sushmita Sridhar, Sally Forrest, Derek Pickard, Claire Cormie, Emily Lees, Nicholas R Thomson, Gordon Dougan, View ORCID ProfileStephen Baker
doi: https://doi.org/10.1101/2021.05.06.443048
Sushmita Sridhar
aUniversity of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge, UK
bDepartment of Medicine, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge, UK
cWellcome Sanger Institute, Hinxton, UK
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Sally Forrest
aUniversity of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge, UK
bDepartment of Medicine, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge, UK
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Derek Pickard
aUniversity of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge, UK
bDepartment of Medicine, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge, UK
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Claire Cormie
aUniversity of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge, UK
bDepartment of Medicine, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge, UK
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Emily Lees
dDepartment of Paediatrics, University of Oxford, UK
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Nicholas R Thomson
cWellcome Sanger Institute, Hinxton, UK
eDepartment of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK
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Gordon Dougan
aUniversity of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge, UK
bDepartment of Medicine, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge, UK
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Stephen Baker
aUniversity of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge, UK
bDepartment of Medicine, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge, UK
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  • ORCID record for Stephen Baker
  • For correspondence: sgb47@medschl.cam.ac.uk
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Abstract

Antimicrobial resistance (AMR) is a pressing global health crisis, which has been fuelled by the sustained use of certain classes of antimicrobials, including fluoroquinolones. While the genetic mutations responsible for decreased fluoroquinolone (ciprofloxacin) susceptibility are known, the implications of ciprofloxacin exposure on bacterial growth, survival, and interactions with host cells are not well described. Aiming to understand the influence of inhibitory concentrations of ciprofloxacin in vitro, we subjected three clinical isolates of S. Typhimurium to differing concentrations of ciprofloxacin, dependent on their minimum inhibitory concentrations (MIC), and assessed the impact on bacterial growth, morphology, and transcription. We further investigated the differential morphology and transcription that occurred following ciprofloxacin exposure and measured the ability of ciprofloxacin-treated bacteria to invade and replicate in host cells. We found that ciprofloxacin-exposed S. Typhimurium are able to recover from inhibitory concentrations of ciprofloxacin, and that the drug induces specific morphological and transcriptional signatures associated with the bacterial SOS response, DNA repair, and intracellular survival. In addition, ciprofloxacin-treated S. Typhimurium have increased capacity for intracellular replication in comparison to untreated organisms. These data suggest that S. Typhimurium undergoes an adaptive response under ciprofloxacin perturbation that promotes cellular survival, a consequence that may justify more measured use of ciprofloxacin for Salmonella infections. The combination of multiple experimental approaches provides new insights into the collateral effects that ciprofloxacin and other antimicrobials have on invasive bacterial pathogens.

Importance Antimicrobial resistance is a critical concern in global health. In particular, there is rising resistance to fluoroquinolones, such as ciprofloxacin, a first-line antimicrobial for many Gram-negative pathogens. We investigated the adaptive response of clinical isolates of Salmonella Typhimurium to ciprofloxacin, finding that the bacteria adapt in short timespans to high concentrations of ciprofloxacin in a way that promotes intracellular survival during early infection. Importantly, by studying three clinically relevant isolates, we were able to show that individual isolates respond differently to ciprofloxacin, and for each isolate, there was a heterogeneous response under ciprofloxacin treatment. The heterogeneity that arises from ciprofloxacin exposure may drive survival and proliferation of Salmonella during treatment and lead to drug resistance.

Footnotes

  • ↵* Division of Infectious Diseases, Massachusetts General Hospital, USA

  • ↵# sgb47{at}medschl.cam.ac.uk

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted May 07, 2021.
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Inhibitory concentrations of ciprofloxacin induce an adaptive response promoting the intracellular survival of Salmonella Typhimurium
Sushmita Sridhar, Sally Forrest, Derek Pickard, Claire Cormie, Emily Lees, Nicholas R Thomson, Gordon Dougan, Stephen Baker
bioRxiv 2021.05.06.443048; doi: https://doi.org/10.1101/2021.05.06.443048
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Inhibitory concentrations of ciprofloxacin induce an adaptive response promoting the intracellular survival of Salmonella Typhimurium
Sushmita Sridhar, Sally Forrest, Derek Pickard, Claire Cormie, Emily Lees, Nicholas R Thomson, Gordon Dougan, Stephen Baker
bioRxiv 2021.05.06.443048; doi: https://doi.org/10.1101/2021.05.06.443048

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