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.

Public Health Relevance

H. pylori infection causes peptic ulcer disease and increases the risk of gastric cancer. Peptic ulcer disease and gastric cancer are major causes of illness in Veterans, in the United States and worldwide. H. pylori dwell in the acid-secreting stomach and have evolved unique acid-protective mechanisms to allow stomach infection. Standard triple or quadruple therapies with acid-blocking medicines and antibiotics have become less effective, falling below 80% success rate because of increasing antibiotic resistance. An understanding of how H. pylori infect the stomach will aid the development of new eradication therapies. A possible strategy to replace current therapy is to target genes that allow the bacteria to survive in acid with non-antibiotic compounds. Another possible strategy is to improve control of the pH of the bacterial environment, so that dual therapy with acid inhibition and amoxicillin could be used. This would involve development of drugs with better acid-blocking properties.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01BX001006-06
Application #
8984263
Study Section
Gastroenterology (GAST)
Project Start
2010-10-01
Project End
2018-09-30
Budget Start
2015-10-01
Budget End
2016-09-30
Support Year
6
Fiscal Year
2016
Total Cost
Indirect Cost
Name
VA Greater Los Angels Healthcare System
Department
Type
DUNS #
066689118
City
Los Angeles
State
CA
Country
United States
Zip Code
90073
Sachs, G; Marcus, E A; Wen, Y et al. (2018) Editorial: control of acid secretion. Aliment Pharmacol Ther 48:682-683
Abe, Kazuhiro; Shimokawa, Jun; Naito, Mao et al. (2017) The cryo-EM structure of gastric H+,K+-ATPase with bound BYK99, a high-affinity member of K+-competitive, imidazo[1,2-a]pyridine inhibitors. Sci Rep 7:6632
Habeck, Michael; Tokhtaeva, Elmira; Nadav, Yotam et al. (2016) Selective Assembly of Na,K-ATPase ?2?2 Heterodimers in the Heart: DISTINCT FUNCTIONAL PROPERTIES AND ISOFORM-SELECTIVE INHIBITORS. J Biol Chem 291:23159-23174
Tokhtaeva, Elmira; Sun, Haying; Deiss-Yehiely, Nimrod et al. (2016) The O-glycosylated ectodomain of FXYD5 impairs adhesion by disrupting cell-cell trans-dimerization of Na,K-ATPase ?1 subunits. J Cell Sci 129:2394-406
Marcus, Elizabeth A; Sachs, George; Wen, Yi et al. (2016) Phosphorylation-dependent and Phosphorylation-independent Regulation of Helicobacter pylori Acid Acclimation by the ArsRS Two-component System. Helicobacter 21:69-81
Marcus, Elizabeth A; Tokhtaeva, Elmira; Turdikulova, Shahlo et al. (2016) Septin oligomerization regulates persistent expression of ErbB2/HER2 in gastric cancer cells. Biochem J 473:1703-18
Marcus, Elizabeth A; Sachs, George; Scott, David R (2016) Eradication of Helicobacter pylori Infection. Curr Gastroenterol Rep 18:33
Scott, David R; Marcus, Elizabeth A; Sachs, George (2016) Vonoprazan: MarKed Competition for PPIs? Dig Dis Sci 61:1783-4
Marcus, E A; Sachs, G; Scott, D R (2015) Colloidal bismuth subcitrate impedes proton entry into Helicobacter pylori and increases the efficacy of growth-dependent antibiotics. Aliment Pharmacol Ther 42:922-33
Scott, D R; Munson, K B; Marcus, E A et al. (2015) The binding selectivity of vonoprazan (TAK-438) to the gastric H+, K+ -ATPase. Aliment Pharmacol Ther 42:1315-26

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