The Communication Factor EDF and the Toxin–Antitoxin Module mazEF Determine the Mode of Action of Antibiotics

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Abstract
It was recently reported that the production of Reactive Oxygen Species (ROS) is a common mechanism of cell death induced by bactericidal antibiotics. Here we show that triggering the Escherichia coli chromosomal toxin–antitoxin system mazEF is an additional determinant in the mode of action of some antibiotics. We treated E. coli cultures by antibiotics belonging to one of two groups: (i) Inhibitors of transcription and/or translation, and (ii) DNA damaging. We found that antibiotics of both groups caused: (i) mazEF-mediated cell death, and (ii) the production of ROS through MazF action. However, only antibiotics of the first group caused mazEF-mediated cell death that is ROS-dependent, whereas those of the second group caused mazEF-mediated cell death by an ROS-independent pathway. Furthermore, our results showed that the mode of action of antibiotics was determined by the ability of E. coli cells to communicate through the signaling molecule Extracellular Death Factor (EDF) participating in mazEF induction. The modes of action of antibiotics are mainly characterized by the effect they have on their targets. Recently, it was reported that the formation of Reactive Oxygen Species (ROS) is a common downstream mechanism of antibiotics that leads to cell death—called bactericidal—while the bacteriostatic antibiotics—causing growth arrest—do not cause ROS formation. We uncovered complexity in how an antibiotic kills by linking antibiotic action and ROS formation with the bacterial toxin–antitoxin system called mazEF, a system by which bacteria are known to commit suicide. We show that mazEF affects antibiotics cell death through ROS-dependent and ROS-independent mechanisms. Following antibiotic treatment, the communication signaling peptide, called Extracellular Death Factor (EDF), mediates cell death through the activation of the mazEF system. Our study challenges the classical division between bacteriostatic and bactericidal antibiotics and provides evidence that antibiotics' mode of action is determined by the ability of the bacteria to communicate through the signaling peptide EDF.

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