Bacterial Systems Biology and Anti Microbial Resistance

We combine bacteriology, microfluidics, microscopy, and mathematical modelling to better understand how the bacterium Escherichia coli responds to antibiotics that cause DNA damage.

Team members : 

  • Meriem El Karoui (Team Leader, DR CNRS)
  • Léo Caulat (AGPR, ENS Paris-Saclay)
  • Mélissa Poncet (IR)
  • Tatiana Coelho (AI)
  • Louise Goossens (PhD student, co-supervision, University of Edinburgh)
  • Achille Fraisse (PhD student, co-supervision, University of Edinburgh)
  • Dorian Joffres (M2 intern)
  • The-Phuong Nguyen (M2 intern)

Contact: meriem.el_karoui at ens-paris-saclay.fr

Antimicrobial resistance is a major health issue which threatens medicine as we know it, potentially making routine surgery or cancer treatment highly risky. Whilst the targets of antibiotics are usually well defined, surprisingly little is known about how antibiotic efficacy depends on the physiological state of bacteria. Yet, bacteria can grow under diverse conditions and exhibit high phenotypic heterogeneity at the single-cell level in their responses to antibiotics, leading to transient antibiotic tolerance and long-term resistance. The objective of our team is to characterise experimentally and quantitatively how the survival of bacteria under antibiotic exposure depends on their physiological state. We use Escherichia coli as our model bacterium and employ laboratory strains, such as K-12 MG1655, and Uropathogenic (UPEC) strains responsible for Urinary Tract Infections (UTI). We focus mainly on antibiotics that cause DNA damage, such as the fluoroquinolone ciprofloxacin. 

Bacteria can grow at vastly different rates: for example, E. coli can divide every twenty minutes in urine during UTIs, or much more slowly (every 3 hours) in the gut. Moreover, cells within an isogenic population differ phenotypically due to stochastic and environmental factors. This phenotypic heterogeneity can enable a subset of cells to increase their survival probability under antibiotic exposure. One example of this phenomenon is bacterial persistence, in which a subset of cells enters a dormant, drug-tolerant state without being resistant. This phenomenon has attracted considerable attention, yet there has been much less focus on how changes in the growth rates of actively dividing bacteria affect susceptibility to antibiotics. Indeed, heterogeneity in growth and gene expression could lead to transient “resilience,” in which cells survive without necessarily entering dormancy, as a result of variation in their individual growth rates. We therefore aim to quantify the response to DNA damage at the single-cell level as a function of growth rate and to identify the underlying molecular mechanisms. 

Furthermore, in natural environments, stressors may have a more substantial impact on bacterial cell physiology than simply a growth shift. An important example is the switch in bacteria from a cell-walled to a wall-deficient state, often referred to as cell wall-deficient bacteria (CWDB). CWDBs of E. coli have been found in macrophages and in the urine of patients with recurrent UTIs. They are thought to arise as a protective mechanism against cell-wall-targeting antibiotics to which they become resistant, but they can revert to the walled form when these antibiotics are removed. They remain metabolically active, yet they multiply more slowly than their walled counterparts and through different mechanisms. However, the susceptibility of CWDBs to antibiotics that do not target cell wall synthesis, and in particular to ciprofloxacin and DNA-damaging agents, has not been well characterised and constitutes our second research theme. 

In the context of UTI, the bacteria colonise and infect the urinary tract. UTIs are classified as lower UTIs (cystitis), which involve infection of the bladder, and upper UTIs (pyelonephritis), which involve infection of the kidney. In both types of infection, bacteria colonise the epithelium of different organs. In these complex environments, the sensitivity and response of bacteria to antibiotics are likely altered, but this has not yet been explored in detail. Our third research theme is therefore to understand E. coli response and tolerance to ciprofloxacin in the urinary tract, using bladder and ureter microtissues to model infection.  
The team combines expertise in molecular bacteriology, quantitative microscopy (epifluorescence, HILO, single-molecule tracking) and image analysis using deep neural network algorithms, as well as microfluidics and mathematical modelling.  

Recent publications: 

1.    Single-molecule imaging of RecB in vivo reveals dynamics of DNA Double Strand Break repair in Escherichia coli. Daniel Thédié, Alessia Lepore, Lorna McLaren, Meriem El Karoui. bioRxiv 2024.12.18.629153; doi: https://doi.org/10.1101/2024.12.18.629153

2.    Deciphering the Replication-Division Coordination in E. coli: A Unified Mathematical framework for Systematic Model Comparison. A. Perrin, M. Doumic, M. El Karoui and S. Méléard. bioRxiv 2025.07.25.666816, doi: https://doi.org/10.1101/2025.07.25.666816

3.    Suppression of bacterial cell death underlies the antagonistic interaction between ciprofloxacin and tetracycline in Escherichia coli. J. Broughton, A. Fraisse, and M. El Karoui. Mol Syst Biol. 2026 Jan;22(1):102-118. doi: 10.1038/s44320-025-00162-w

4.    In vivo single-molecule imaging of RecB reveals efficient repair of DNA damage in Escherichia coli. A. Lepore, D. Thédié, L. McLaren, B. Azeroglu, O.J. Pambos, A. N. Kapanidis, M. El Karoui. Nucleic Acids Research, Volume 53, Issue 10, 10 June 2025 DOI: 10.1093/nar/gkaf454

5.    Kalita I., Iosub I.A., Granneman S., & M. El Karoui. 2024.An Hfq-dependent post-transcriptional mechanism fine tunes RecB expression in Escherichia coli eLife13:RP94918 https://doi.org/10.7554/eLife.94918.22024. 

Current collaborations
•    Sylvie Méléard and Marie Doumic, Alexandre Perrin, Ecole polytechnique (ERC SINGER)
•    Imane El Méouche, INSERM, Sakina Bensalem, ENS Paris Saclay (ANR RESISTANTE)
•    Diego Oyarzun, Jamie Davies and Maddie Moule. University of Edinburgh
•    Mannish Kushwaha (INRAE), Matthias Fuegger, Thomas Nowak (ENS-Paris-Saclay)