Gastric infection by Helicobacter pylori

Abstract

Helicobacter pylori infection causes chronic active gastritis, ulcer disease, and gastric cancer. Current eradication regimens use a proton pump inhibitor (PPI) and two antibiotics. Triple therapy now has a success rate less than 80%, below the cutoff for efficacious eradication. Antibiotic resistance, inconsistent acid control by PPIs, and poor patient compliance contribute to the failure rate. H. pylori is a neutralophile that has developed special acid acclimation mechanisms to colonize its acidic gastric niche. Identifying the components of these mechanisms will provide novel bactericidal drug targets. Alternatively, better 24-hour acid control would increase the efficacy of antibiotics, leading to dual therapy with improved PPIs and amoxicillin. Studies of acid acclimation by H. pylori have identified several potential eradication targets including UreI, alpha-carbonic anhydrase, and a two-component system. Continuing improvement of PPIs has led to the development of at least three candidate drugs with improved 24-hour acid control.

Figure 1

A model of HP0165/HP0166 regulation of periplasmic pH of Helicobacter pylori. Under acidic conditions, urea enters the periplasm through the outer membrane via porins. Urea entry into the cytoplasm is accelerated by the H⁺-gated urea channel, UreI, increasing urease activity. Periplasmic acidity also activates the histidine kinase sensor, HP0165, by phosphate transfer to the response element, HP0166, thus increasing transcription of the “acid acclimation” genes, with the exception of hypB and aspA. Arginase produces cytoplasmic urea and the amidases and aspartase, cytoplasmic NH₃. Urease activity is increased by nickel insertion into the UreA/UreB apoenzyme by UreE, F, G, and H in concert with HypA and HypB, hydrogenase accessory proteins. Cytoplasmic urease generates 2NH₃ + H₂CO₃^- which is converted to CO₂ + H₂O by cytoplasmic β-carbonic anhydrase. The membrane-permeant NH₃ and CO₂ diffuse into the periplasm. The CO₂ is converted to H⁺ + HCO₃^- by the membrane-bound periplasmic α-carbonic anhydrase that buffers the periplasm to pH about 6.1. The NH₃ absorbs the proton released by carbonic anhydrase and the other NH₃ is able to absorb entering protons or can alkalinize the medium. The cooperative upregulation of these genes and the role of the HP0165/HP0166 two-component system illustrate not only that the organism is exposed to acidic pH, but also that several genes of this regulon are involved in maintaining gastric infection.