# Single-cell heterogeneity underpins antagonistic antibiotic interactions

## TL;DR

This paper shows how single-cell responses to antibiotic combinations can lead to treatment failure due to cellular heterogeneity.

## Contribution

The study reveals how the SOS response and drug interactions create survival heterogeneity in E. coli under antibiotic treatment.

## Key findings

- Ciprofloxacin and tetracycline combination leads to heterogeneous survival in E. coli cells.
- Moderate SOS response levels are linked to cell survival, while high levels are found in dying cells.
- Tetracycline increases survival in the low-SOS subpopulation, contributing to antagonistic drug effects.

## Abstract

Using combinations of existing antibiotics is a promising strategy to treat bacterial infections. Although some drugs act synergistically, other drug combinations inhibit microbial growth less than what is expected from their individual effects. Ciprofloxacin and tetracycline display such antagonistic interaction. In a new study, Broughton and colleagues (Broughton et al, 2025) used single-cell microfluidics to show that exposing E. coli cells to a combination of ciprofloxacin and tetracycline results in highly heterogeneous outcomes. The survival of single cells is linked to the expression of moderate levels of the SOS response, which fixes the double-strand DNA breaks caused by ciprofloxacin. High expression of the SOS response was found only among dying cells. Tetracycline then counteracts ciprofloxacin by increasing the proportion of cells that survive treatment within the low-SOS subpopulation. These findings highlight the importance of single-cell studies in understanding the phenotypic heterogeneity that emerges during antibiotic responses, which decide the success of treatments.

J. Carvalho and D. Schultz discuss the study by Broughton et al, in this issue of Molecular Systems Biology, on the heterogeneous responses of individual E. coli to a combination of antibiotics, contributing to their antagonistic interaction.