Purine biosynthesis as a therapeutic target for Helicobacter pylori infection

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DESCRIPTION (provided by applicant): Helicobacter pylori is a Gram-negative, microaerophilic bacterium and one of the most common human bacterial pathogens, chronically infecting the gastric mucosa of approximately half of the world's population. While infection can be asymptomatic, H. pylori can cause chronic inflammation, duodenal and gastric ulcers, gastric mucosa-associated lymphoid tissue (MALT) lymphoma, and gastric cancer. As the causative agent of human cancer, H. pylori is considered a class I carcinogen by the WHO. H. pylori infection persists throughout life unless the organism is eradicated. Antimicrobial therapies against H. pylori are available, but they require multidrug regimens in combination with proton-pump inhibitors, over the course of at least 7 days. In addition to problems with patient compliance, resistance to commonly used antibiotics is becoming an important problem. Thus, there is an urgent need for new antimicrobials to treat H. pylori. Even so, successful eradication via antimicrobial therapy does not protect against subsequent infection. Another approach to combat H. pylori is vaccination. The goal of the current Exploratory/Developmental Research Grant is to evaluate the enzyme inosine 5'- monophosphate dehydrogenase (IMPDH), which is involved in purine biosynthesis, as a viable drug target for H. pylori. We have already recognized IMPDH inhibitors that can inhibit the H. pylori enzyme and growth of H. pylori in vitro. Here we will evaluate newer compounds that display no toxicity at 250 mg/kg when given orally to mice and have been already been tested by our colleague Dr. Lizabeth Hedstrom (Brandeis University) in a mouse model of cryptosporidiosis. We will test these for growth inhibition of H. pylori in vitro and in a mouse model of H. pylori infection. We have also constructed an H. pylori strain with a deletion in the gene (guaB) that encodes IMPDH. This strain was shown to be auxotrophic and lack IMPDH activity. We will test whether the H. pylori ?guaB mutant is attenuated in a mouse model of infection. Subsequently, it will be evaluated as a live vaccine to provide protection against H. pylori infection. The experiments in this proposal are the appropriate first steps to determine whether purine biosynthesis represents a viable therapeutic target for H. pylori.