Iron-dependent essential genes in Salmonella Typhimurium

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.Electronic supplementary materialThe online version of this article (10.1186/s12864-018-4986-1) contains supplementary material, which is available to authorized users.

Probabilistic identification of bacterial essential genes via insertion density using TraDIS data with Tn5 libraries

“…viability). They are usually defined operationally in natural or specific conditions ( Karash and Kwon, 2018 ) with those genes required for basic metabolism or growth in the natural host or environment identified as essential ( Tateishi et al , 2020 ). Genes required for specific biological processes like motility, drug resistance, cell division etc.…”

Effect of Nutritional Determinants and TonB on the Natural Transformation of Riemerella anatipestifer

“…In our study, the natural transformation was inhibited by adding 100 μM Dip, and the transformation frequency was restored gradually by the supplementation with Fe(NO 3 ) 3 . Dip is reported to be a chelator of divalent cations, which has been widely used in many studies to foster iron starvation ( Lu et al, 2013 ; Yan et al, 2013 ; Karash and Kwon, 2018 ). It was suggested that the natural transformation of R. anatipestifer ATCC11845 could be affected by iron, implying that energy generation, as well as nucleotide synthesis, are important for the process of natural transformation.…”

Genome-wide fitness analysis identifies genes required for in vitro growth and macrophage infection by African and Global Epidemic pathovariants of Salmonella Enteritidis

“…The relative changes in abundance of each transposon mutant before and after the treatment reflects the contribution of each gene to survival and adaptation to a particular environment. TIS has been successfully used in various bacteria species to define genetic requirements for bacterial viability and fitness during in vitro growth and following infection of mammalian hosts and host cells [25][26][27][28][29][30][31][32][33]. Our findings delineate the fitness landscapes of GEC P125109 and CEAC D7795 during conditions relevant to mammalian host infection.…”