Abstract
BackgroundThe molecular mechanisms underlying bacterial cell death due to stresses or bactericidal antibiotics are complex and remain puzzling. Due to the current crisis of antibiotic resistance, development of effective antibiotics is urgently required. Previously, it has been shown that iron is required for effective killing of bacterial cells by numerous bactericidal antibiotics.ResultsWe investigated the death or growth inhibition of S. Typhimurium under iron-restricted conditions, following disruption of essential genes, by transposon mutagenesis using transposon sequencing (Tn-seq). Our high-resolution Tn-seq analysis revealed that transposon mutants of S. Typhimurium with insertions in essential genes escaped immediate killing or growth inhibition under iron-restricted conditions for approximately one-third of all previously known essential genes. Based on this result, we classified all essential genes into two categories, iron-dependent essential genes, for which the insertion mutants can grow slowly if iron is restricted, and iron-independent essential genes, for which the mutants become nonviable regardless of iron concentration. The iron-dependency of the iron-dependent essential genes was further validated by the fact that the relative abundance of these essential gene mutants increased further with more severe iron restrictions. Our unexpected observation can be explained well by the common killing mechanisms of bactericidal antibiotics via production of reactive oxygen species (ROS). In this model, iron restriction would inhibit production of ROS, leading to reduced killing activity following blocking of essential gene functions. Interestingly, the targets of most antibiotics currently in use clinically are iron-dependent essential genes.ConclusionsOur result suggests that targeting iron-independent essential genes may be a better strategy for future antibiotic development, because blocking their essential gene functions would lead to immediate cell death regardless of the iron concentration. This work expands our knowledge on the role of iron to a broad range of essential functions and pathways, providing novel insights for development of more effective antibiotics.
Highlights
The molecular mechanisms underlying bacterial cell death due to stresses or bactericidal antibiotics are complex and remain puzzling
Kohanski et al [5] proposed that bactericidal antibiotics, regardless of their molecular targets, induce production of reactive oxygen species (ROS) that contributes to cell death, and demonstrated that the death process can Karash and Kwon BMC Genomics (2018) 19:610 be mitigated via iron chelators
Immune cells produce ROS to kill bacterial pathogens [9]. Despite these numerous evidences on the role of ROS in bacterial cell death, it is unknown if this role of ROS can be extended to all death processes in bacterial cells, and if not, what the scope of the essential genes is for which ROS production contributes to cellular death when they are inactivated or their protein functions are blocked
Summary
The molecular mechanisms underlying bacterial cell death due to stresses or bactericidal antibiotics are complex and remain puzzling. Kohanski et al [5] proposed that bactericidal antibiotics, regardless of their molecular targets, induce production of ROS that contributes to cell death, and demonstrated that the death process can Karash and Kwon BMC Genomics (2018) 19:610 be mitigated via iron chelators. This model asserts that upon antibiotic-target interactions, consecutive specific intracellular events induce ROS formation, hydroxyl radical, via Fenton reaction through the process that involves TCA cycle-NADH depletion and destabilization of Fe-S clusters [5, 6]. Despite these numerous evidences on the role of ROS in bacterial cell death, it is unknown if this role of ROS can be extended to all death processes in bacterial cells, and if not, what the scope of the essential genes is for which ROS production contributes to cellular death when they are inactivated or their protein functions are blocked
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