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Phase variation controls expression of Salmonella lipopolysaccharide modification genes by a DNA methylation-dependent mechanism.

ABSTRACT: The O-antigen of Salmonella lipopolysaccharide is a major antigenic determinant and its chemical composition forms the basis for Salmonella serotyping. Modifications of the O-antigen that can affect the serotype include those carried out by the products of glycosyltransferase operons (gtr), which are present on specific Salmonella and phage genomes. Here we show that expression of the gtr genes encoded by phage P22 that confers the O1 serotype is under the control of phase variation. This phase variation occurs by a novel epigenetic mechanism requiring OxyR in conjunction with the DNA methyltransferase Dam. OxyR is an activator or a repressor of the system depending on which of its two binding sites in the gtr regulatory region is occupied. Binding is decreased by methylation at Dam target sequences in either site, and this confers heritability of the expression state to the system. Most Salmonella gtr operons share the key regulatory elements that are identified here as essential for this epigenetic phase variation.

SUBMITTER: Broadbent SE

PROVIDER: S-EPMC2909390 | biostudies-literature | 2010 Jul

REPOSITORIES: biostudies-literature

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Phase variation controls expression of Salmonella lipopolysaccharide modification genes by a DNA methylation-dependent mechanism.

Broadbent S E SE Davies M R MR van der Woude M W MW

Molecular microbiology 20100512 2

The O-antigen of Salmonella lipopolysaccharide is a major antigenic determinant and its chemical composition forms the basis for Salmonella serotyping. Modifications of the O-antigen that can affect the serotype include those carried out by the products of glycosyltransferase operons (gtr), which are present on specific Salmonella and phage genomes. Here we show that expression of the gtr genes encoded by phage P22 that confers the O1 serotype is under the control of phase variation. This phase ...[more]

PMID: 20487280

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Project description: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.

Dataset Information

Phase variation controls expression of Salmonella lipopolysaccharide modification genes by a DNA methylation-dependent mechanism.

Publications

Phase variation controls expression of Salmonella lipopolysaccharide modification genes by a DNA methylation-dependent mechanism.

Similar Datasets

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