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A Conditionally Lethal Helicobacter Pylori Strain
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Vanderbilt University researchers have characterized an H. pylori specific gene, dapE, which can be used to generate novel, targeted therapeutics for H. pylori-induced infections in the stomach. The gene encodes an enzyme responsible for the synthesis of the amino acid lysine. Most bacterial species have redundant pathways for amino acid synthesis because they are essential for life, however H. pylori is unique in that it has only one pathway for lysine biosynthesis. In an era when antibiotic resistance has become a significant hurdle in combating bacterial infections, this gene target provides a new, antibiotic independent, modality to combat H. pylori infection. Conditionally-mutant DapE H. pylori strains can be licensed directly for use as a research tool.
H. pylori infection has been directly linked to the development of gastric cancer which is the second leading cause of cancer related death worldwide. As a result, the World Health Organization (WHO) has classified H. pylori as a class I carcinogen. Eradication of this gastric pathogen has been shown to reduce the incidence of peptic ulcer disease and gastric cancer. Traditionally H. pylori is eradicated by a regimen of triple or quadruple antibiotic therapy in combination with a proton pump inhibitor. However, due to the high prevalence of H. pylori infection (~90% worldwide), treating every patient with antibiotics increases the risk of generating antibiotic resistant strains of H. pylori and adversely affecting gastrointestinal microflora. Therefore, Vanderbilt researchers have identified the dapE gene which is unique to H. pylori and can be used to deliver a targeted therapeutic that can be switched off on demand.
How it Works:
The H. pylori dapE gene encodes for an N-succinyl-L-diaminopimelic acid desuccinylase, an enzyme required for the generation of the amino acid lysine. H. pylori requires lysine to generate peptidoglycan, which is an integral component of the bacterial cell wall. The dapE gene is the only H. pylori gene that encodes for lysine synthesis and thus disruption of this gene or gene product is lethal.
Therapeutics Research: The dapE gene vectors can be incorporated into other bacterial strains such as E.coli to generate large volumes of recombinant N-succinyl-L-diaminopimelic acid desuccinylase. The dapE gene product can then be used to design specific inhibitors to render it inert.
Vaccine Research Strategies: Animals can be infected with the dapE mutant strain of H. pylori and supplemented with an enzyme substrate to maintain H. pylori viability until sufficient immune responses are generated. The H. pylori strain can then quickly be eradicated by stopping supplementation.
Inventors:Martin BlaserMikio Karita