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Published on: January 27, 2021
Lethal mutations in the isoprenoid pathway of Salmonella enterica
Rita M Cornish1, John R Roth, C Dale Poulter
1Department of Chemistry, University of Utah, Salt Lake City, Utah 84112, USA.
Abstract:
Essential isoprenoid compounds are synthesized using the 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway in many gram-negative bacteria, some gram-positive bacteria, some apicomplexan parasites, and plant chloroplasts. The alternative mevalonate pathway is found in archaea and eukaryotes, including cytosolic biosynthesis in plants. The existence of orthogonal essential pathways in eukaryotes and bacteria makes the MEP pathway an attractive target for the development of antimicrobial agents. A system is described for identifying mutations in the MEP pathway of Salmonella enterica serovar Typhimurium. Using this system, point mutations induced by diethyl sulfate were found in the all genes of the essential MEP pathway and also in genes involved in uptake of methylerythritol. Curiously, none of the MEP pathway genes could be identified in the same parent strain by transposon mutagenesis, despite extensive searches. The results complement the biochemical and bioinformatic approaches to the elucidation of the genes involved in the MEP pathway and also identify key residues for activity in the enzymes of the pathway.
Insights
The 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway is essential for bacteria. Researchers identified mutations in Salmonella Typhimurium
Area of Science:
- Microbiology
- Biochemistry
- Genetics
Background:
- Essential isoprenoid compounds are synthesized via the 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway in bacteria and plant chloroplasts.
- An alternative mevalonate pathway exists in archaea and eukaryotes, presenting the MEP pathway as a potential antimicrobial target.
Purpose of the Study:
- To develop a system for identifying mutations within the MEP pathway of Salmonella enterica serovar Typhimurium.
- To identify key residues crucial for enzyme activity within the MEP pathway.
Main Methods:
- Induction of point mutations using diethyl sulfate in Salmonella Typhimurium.
- Screening for mutations in MEP pathway genes and methylerythritol uptake genes.
- Comparison with transposon mutagenesis approaches.
Main Results:
- Diethyl sulfate mutagenesis successfully identified point mutations in all essential MEP pathway genes and methylerythritol uptake genes.
- Transposon mutagenesis failed to identify any MEP pathway genes in the same bacterial strain.
- The study complements existing biochemical and bioinformatic data on MEP pathway genes.
Conclusions:
- The developed system is effective for identifying mutations in the essential MEP pathway of Salmonella Typhimurium.
- The findings highlight the utility of chemical mutagenesis for MEP pathway gene discovery.
- Key residues for enzyme activity in the MEP pathway were identified, aiding future drug development.
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