Phage regulation and persister cell formation upon ciprofloxacin treatment via the toxin TisB in Salmonella Typhimurium

Introduction

Persisters are drug-tolerant cells that survive bactericidal concentrations of antibiotics, therefore playing an important role in clinical therapy failure [1]. Mechanisms influencing bacterial survival during treatment with antibiotics include the activity of bacterial toxins, induction of prophages, and activation of stress responses [2, 3].

Material/method

We examined the effects of a tisB toxin deletion mutant in Salmonella Typhimurium on the ATP concentrations during treatment with four-fold the MIC of ciprofloxacin. Furthermore, we also examined the TisB-dependent induction of the prophages and their impact on persister cell formation comparing a phage-free variant of the wild type strain in a ∆tisB background.

Results

Deletion of tisB significantly increased ATP concentration and SOS response when exposed to ciprofloxacin, with a reduction in the formation of persistent cells. Interestingly, a 90-fold reduction in bacterial survival was observed four hours after challenging the phage-carrying ∆tisB strain with ciprofloxacin. In contrast, deletion of all prophages in the tisB background slowed initial killing and had a less significant impact on drug persistence.

Discussion

The SOS response is controlled by RecA, which requires ATP for its activity. We suggest that TisB inhibits ATP formation, and interferes with DNA repair responses. This significantly reduces the SOS response-dependent prophage induction and thus increases persister cell formation.

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