Activation of a built-in bacterial programmed cell death system as a novel mechanism of action of some antibiotics

The modes of action of antibiotics are mainly characterized by their effects on their targets. Previously,^1,2 and in a recent paper,³ we have reported our discovery of a new mechanism for the action of some antibiotics. Rather than directly interfering with a vital bacterial pathway, these antibiotics act by triggering the bacterial toxin-antitoxin chromosomal module mazEF, thereby causing the bacteria to commit suicide. We also showed that antibiotics that inhibit transcription and/or translation cause mazEF-mediated cell death by forming Reactive Oxygen Species (ROS).³ Moreover, we found that after treatment by such antibiotics, the mazEF system cannot be activated, and thus ROS cannot be formed, without the presence of communication signaling peptide called the Extracellular Death Factor (EDF). Our results challenge the classical division between bacteriostatic and bactericidal antibiotics. Our study further provides evidence that mode of action of antibiotics may also be determined by the ability of the bacteria to communicate through the signaling peptide EDF. In this Addendum article we present a model of how the presence of some antibiotics may result in this novel downstream pathway.