How antibiotics kill bacteria: from targets to networks

Key Points Substantial progress has been made in our understanding of the mechanistic details of bacterial cell death induced by bactericidal antibiotics. In this Review, we discuss how bactericidal antibiotics kill bacteria by inhibiting essential cellular processes and by activating cellular response pathways that contribute to cell death. Bactericidal antibiotics target a diverse set of biomolecules for inhibition to achieve cell death, including DNA topoisomerases (involved in modulating DNA topology), RNA polymerase (involved in RNA transcription), penicillin-binding proteins, transglycosylases and peptidoglycan building blocks (involved in cell wall homeostasis), as well as ribosomes (involved in protein synthesis). Treatment with lethal concentrations of bactericidal antibiotics has been shown to trigger several stress responses and additional off-target effects in the face of drug-induced stress. These responses include the recently described oxidative damage cellular death pathway, which is commonly induced by all major classes of bactericidal antibiotics and involves alterations in metabolism (that is, central carbon and iron) that culminate in the production of cytotoxic superoxide and hydroxyl radicals. Several approaches have been employed to provide a more complete understanding of the sequences of events underlying bactericidal antibiotic-induced cell death for each drug class, beginning with the binding of a drug molecule to its primary target. Biological network analysis provides a powerful method for predicting and characterizing the potential interplay between genes and proteins functionally interacting to coordinate bacterial stress response pathways. Given the threat and continued rise of antibiotic-resistant bacteria, it is crucial that improvements be made to current antibacterial therapies and that new antibiotics are developed. Antibiotic network biology provides a means to comparatively study the response mechanisms of diverse bacterial species to various bactericidal drug classes to predict the responses of pathogenic bacteria to available treatment regimens, and to determine the mode of action of new antibacterial agents. Bacterial responses to antibiotics are complex and involve many genetic and biochemical pathways. This Review describes the effects of bactericidal antibiotics on bacterial cellular processes, the associated responses that contribute to killing and recent insights into these processes revealed through the study