Acid Adaptation Targets for Eradication of Helicobacter pylori

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DESCRIPTION (provided by applicant): Helicobacter pylori infects the stomach of half of the world's population. This infection is a primary cause of peptic ulcer disease and a high risk factor for gastric cancer. Therefore, eradication of H. pylori infection leads to ulcer healing and lowers the risk of gastric cancer. Unil the discovery of H. pylori, it was thought that stomach acid presented an inhospitable environment for bacterial infection. However, H. pylori has uniquely developed the means of surviving and growing on the acidic surface of the human stomach, a process termed acid acclimation. Disruption of this process leads to loss of survival in acid; therefore, the components of this process would provide novel targets for eradication therapy. Current eradication therapies require the use of antibiotics along with acid-inhibitory drugs. The successful eradication by these therapies is decreasing because of increasing antibiotic resistance, resulting in a response rate of ~70% in the USA. The growth-dependent antibiotics clarithromycin or amoxicillin are not effective unless bacteria are in growth phase. Improving acid inhibition should improve therapeutic outcome. In the first aim, we hypothesize that inhibition of acid secretion increases the number of bacteria in growth phase, making them sensitive to growth-dependent antibiotics, necessitating the requirement for administration of acid-inhibitory compounds, in addition to antibiotics for successful eradication. The finding that slow omeprazole metabolizers respond with much improved acid control and effective eradication with omeprazole and amoxicillin alone, suggests that improved acid inhibition increases the sensitivity of the organism to growth-dependent antibiotics. From this it follows that, with more consistent and greater elevation of intragastric pH, more organisms are in the antibiotic-sensitive growth phase rather than the resistant stationary phase. Maintenance of an elevated pH for both day and night should put almost all H. pylori in growth phase. Therefore, the effect of profound acid inhibition on the bactericidal effect of amoxicillin will be tested in ivo in the gerbil. UreI, a proton-gated urea channel, forms an inner membrane complex at least with urease and the Ni2+ insertion subunits. Formation of this complex and interaction of other proteins that comprise the complex will be identified using state-of-the-art MS/MS techniques. The novel crystal structure of UreI will be used to identify the cytoplasmic loop binding sites of the proteins interacting with the channel. In the future, the loops identified as essential can be exploited for the development of novel and specific inhibitors of UreI complex formation. Successful completion of this aim could lead to an H. pylori-specific mono-therapy for eradication.