Purine biosynthesis as a therapeutic target for Helicobacter pylori infection

Emory University, Atlanta GA

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Abstract

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), involved in purine biosynthesis, as a viable drug target for H. pylori. We have already recognized compounds that can inhibit H. pylori IMPDH and the 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. Lizbeth 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. We have shown that this mutant is auxotrophic and lacks IMPDH activity. Here, 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. If vaccination is effective, the mechanism of protection and protective antigens will be identified. If the ¿guaB mutant is not sufficiently attenuated other purine biosynthetic mutants with different auxotrophic requirements will be tested. The experiments in this proposal are the appropriate first steps to determine whether purine biosynthesis represents a viable therapeutic target for H. pylori.