Iron-dependent essential genes in Salmonella Typhimurium
Abstract Background The 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...
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doaj-2e2dbd40793344859a3eb923a74a40e02020-11-25T01:32:44ZengBMCBMC Genomics1471-21642018-08-0119111310.1186/s12864-018-4986-1Iron-dependent essential genes in Salmonella TyphimuriumSardar Karash0Young Min Kwon1Cell and Molecular Biology Program, University of ArkansasCell and Molecular Biology Program, University of ArkansasAbstract Background The 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. Results We 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. Conclusions Our 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.http://link.springer.com/article/10.1186/s12864-018-4986-1Salmonella TyphimuriumEssential genesIron-restrictionReactive oxygen speciesAntibiotic targets |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Sardar Karash Young Min Kwon |
spellingShingle |
Sardar Karash Young Min Kwon Iron-dependent essential genes in Salmonella Typhimurium BMC Genomics Salmonella Typhimurium Essential genes Iron-restriction Reactive oxygen species Antibiotic targets |
author_facet |
Sardar Karash Young Min Kwon |
author_sort |
Sardar Karash |
title |
Iron-dependent essential genes in Salmonella Typhimurium |
title_short |
Iron-dependent essential genes in Salmonella Typhimurium |
title_full |
Iron-dependent essential genes in Salmonella Typhimurium |
title_fullStr |
Iron-dependent essential genes in Salmonella Typhimurium |
title_full_unstemmed |
Iron-dependent essential genes in Salmonella Typhimurium |
title_sort |
iron-dependent essential genes in salmonella typhimurium |
publisher |
BMC |
series |
BMC Genomics |
issn |
1471-2164 |
publishDate |
2018-08-01 |
description |
Abstract Background The 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. Results We 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. Conclusions Our 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. |
topic |
Salmonella Typhimurium Essential genes Iron-restriction Reactive oxygen species Antibiotic targets |
url |
http://link.springer.com/article/10.1186/s12864-018-4986-1 |
work_keys_str_mv |
AT sardarkarash irondependentessentialgenesinsalmonellatyphimurium AT youngminkwon irondependentessentialgenesinsalmonellatyphimurium |
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1725080065555824640 |