Prevention of the Drug Resistance of Helicobacter pylori with 8-Octyl Berberine by Increasing Membrane Permeability and Reducing Motility

Antibiotic resistance is a major problem in the treatment of Helicobacter pylori (H. pylori). Berberine (BBR) has proven to be a promising alternative, though it is less effective than antibiotics. Structurally modified BBR might improve the anti-H. pylori activity. In this study, 8-octyl berberine (OBBR), a BBR derivative, was investigated for the activity and mechanism of action against H. pylori. The results showed that the anti-H. pylori activity of OBBR was significantly higher than that of BBR (about 64 times) and close to amoxicillin. Surprisingly, OBBR was not resistant to H. pylori after 45 generations of induction and showed synergistic effect with amoxicillin in vitro. Regarding the mechanism, OBBR changed the morphological structure of bacteria and caused the outgrowth of phosphatidylserine on the cell membrane, thereby increasing its permeability. Moreover, OBBR inhibited the urease activity, down-regulated the mRNA levels of flagellar genes flaA and flaB, and reduced the motility of H. pylori, thus inhibiting intra-gastric colonization. In an animal model of H. pylori infection, OBBR was found to have a certain effect on the clearance of H. pylori in mice. An excellent anti-H. pylori activity and low drug resistance of OBBR suggest that structural modification of the BBR scaffold may be a favorable approach to the development of promising antibiotics for the treatment of H. pylori.