RT Journal Article SR Electronic T1 Reactive Oxygen Species-Dependent Essential Genes in Salmonella Typhimurium JF bioRxiv FD Cold Spring Harbor Laboratory SP 159921 DO 10.1101/159921 A1 Sardar Karash A1 Young Min Kwon YR 2017 UL http://biorxiv.org/content/early/2017/07/05/159921.abstract AB The molecular mechanisms underlying antibiotic actions on bacterial cells are complex and remain enigmatic. Uncovering these mechanisms is urgently needed to utilize last-resort antibiotics properly and develop novel antibiotics against which development of drug resistance is inherently suppressed. Recently, oxidative stress has been implicated as one common mechanism whereby bactericidal antibiotics kill bacteria. Here, we expand this model to a broader range of essential pathways far beyond the targets of currently used bactericidal antibiotics. This is based on our high-resolution Tn-seq experiment in which transposon mutants with insertions in “essential genes” were rendered non-essential in. S. Typhimurium under iron-restricted conditions for approximately one-third of previously known essential genes. The ROS-dependent nature of these essential genes is further validated by the fact that the relative abundance of the mutants increased with more severe iron restriction. Interestingly, the targets of most antibiotics currently in use clinically, whether bacteriostatic or bactericidal, are ROS-dependent essential genes. Our observation, taken together with the previous studies, suggests that targeting “ROS-independent” essential genes may be better strategy for future antibiotic development, because under iron-restricted host condition it is more likely that (1) its antibiotic activity is not negatively influenced, and (2) development of drug resistance is reduced, due to the absence or reduced level of the ROS component in contrast to the most current antibiotics targeting “ROS-dependent” essential genes. This work expands our knowledge on the role of ROS in general essential pathways and provides novel insights for development of more effective antibiotics with reduced problem of drug resistance development.Importance Due to the crisis of antibiotic resistance, development of novel antibiotics that can avoid drug resistance is urgently required. Recent studies have suggested that ROS formation is a common mechanism contributing to cell death by bactericidal antibiotics. Here we showed that this model is broadly applicable to approximately one-third of all essential genes in S. Typhimurium, far beyond currently known targets of bactericidal antibiotics. This conclusion is supported by our genome-wide study that the transposon mutants with insertions in these “ROS-dependent” essential genes escape antibiotic action partially and can multiply under iron-restriction condition. Our finding suggests that the targeting “ROS-independent” essential genes, in contrast to most current antibiotics targeting “ROS-dependent” essential genes, may be an effective strategy to avoid weakening in antibiotic actions and development of antibiotic resistance in the iron-restricted host environment. The new insights from this study may be critical in developing novel antibiotics with reduced drug resistance.