Selective killing of Helicobacter pylori with pH-responsive helix–coil conformation transitionable antimicrobial polypeptides

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 114; no. 48; pp. 12675 - 12680
• Main Authors: Xiong, Menghua, Bao, Yan, Xu, Xin, Wang, Hua, Han, Zhiyuan, Wang, Zhiyu, Liu, Yeqing, Huang, Songyin, Song, Ziyuan, Chen, Jinjing, Peek, Richard M., Yin, Lichen, Chen, Lin-Feng, Cheng, Jianjun
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 28.11.2017
• Subjects: Amines - chemistry; Animals; Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - pharmacology; Antibacterial activity; Antibiotics; Antimicrobial Cationic Peptides - chemical synthesis; Antimicrobial Cationic Peptides - pharmacology; Bacteria; Coils; Conformation; Disease Models, Animal; Drug resistance; Etiology; Female; Gastric cancer; Gastritis; Glutamic acid; Glutamic Acid - analogs & derivatives; Glutamic Acid - chemical synthesis; Glutamic Acid - pharmacology; Helicobacter Infections - drug therapy; Helicobacter Infections - microbiology; Helicobacter Infections - pathology; Helicobacter pylori; Helicobacter pylori - drug effects; Helicobacter pylori - pathogenicity; Helicobacter pylori - physiology; Hydrogen ions; Hydrogen-Ion Concentration; Mice; Mice, Inbred C57BL; Mice, Inbred ICR; Organ Specificity; pH effects; Physical Sciences; Physiology; Polypeptides; Protein Conformation, alpha-Helical; Proton pump inhibitors; Static Electricity; Stomach; Stomach - drug effects; Stomach - microbiology; Stomach - pathology; Therapy; Tissues; Toxicity; Ulcers; α-helix; H. pylori; antimicrobial peptide; conformational transition; pH sensitiveness
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1710408114

Current clinical treatment of Helicobacter pylori infection, the main etiological factor in the development of gastritis, gastric ulcers, and gastric carcinoma, requires a combination of at least two antibiotics and one proton pump inhibitor. However, such triple therapy suffers from progressively decreased therapeutic efficacy due to the drug resistance and undesired killing of the commensal bacteria due to poor selectivity. Here, we report the development of antimicrobial polypeptide-based monotherapy, which can specifically kill H. pylori under acidic pH in the stomach while inducing minimal toxicity to commensal bacteria under physiological pH. Specifically, we designed a class of pH-sensitive, helix–coil conformation transitionable antimicrobial polypeptides (HCT-AMPs) (PGA)m-r-(PHLG-MHH)n, bearing randomly distributed negatively charged glutamic acid and positively charged poly(γ-6-N-(methyldihexylammonium)hexyl-L-glutamate) (PHLG-MHH) residues. The HCT-AMPs showed unappreciable toxicity at physiological pH when they adopted random coiled conformation. Under acidic condition in the stomach, they transformed to the helical structure and exhibited potent antibacterial activity against H. pylori, including clinically isolated drug-resistant strains. After oral gavage, the HCT-AMPs afforded comparable H. pylori killing efficacy to the triple-therapy approach while inducing minimal toxicity against normal tissues and commensal bacteria, in comparison with the remarkable killing of commensal bacteria by 65% and 86% in the ileal contents and feces, respectively, following triple therapy. This strategy renders an effective approach to specifically target and kill H. pylori in the stomach while not harming the commensal bacteria/normal tissues.