Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 114, Issue 48, Pages 12675-12680Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1710408114
Keywords
antimicrobial peptide; alpha-helix; conformational transition; H. pylori; pH sensitiveness
Categories
Funding
- NSF [CHE 1508710, 1308485]
- NIH [R21AI117080, R01 DK 58587, R01 CA 77955, P01 CA 116087, P30 DK 058404]
- National Natural Science Foundation of China [51403145, 51573123, 51722305]
- Ministry of Science and Technology of China [2016YFA0201200]
- Priority Academic Program Development of Jiangsu Higher Education Institutions
- Division Of Chemistry
- Direct For Mathematical & Physical Scien [1508710] Funding Source: National Science Foundation
- Division Of Chemistry
- Direct For Mathematical & Physical Scien [1308485] Funding Source: National Science Foundation
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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(gamma-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.
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