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

Abstract

Current clinical treatment of 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 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)--(PHLG-MHH), bearing randomly distributed negatively charged glutamic acid and positively charged poly(γ-6--(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 , including clinically isolated drug-resistant strains. After oral gavage, the HCT-AMPs afforded comparable 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 in the stomach while not harming the commensal bacteria/normal tissues.

Transformation of Helicobacter pylori into Coccoid Forms as a Challenge for Research Determining Activity of Antimicrobial Substances

“…The last five articles [38,39,[66][67][68] concerned an activity and morphological effect of peptides against H. pylori. In all, a bactericidal effect was suggested, while the action of peptides on bacteria was demonstrated using microscopy, culture, and fluorescent methods ( Table 5 and Figure 5).…”

Recent Advances and Future Prospects on Adaptive Biomaterials for Antimicrobial Applications

“…Bacteria can inhabit and thrive themselves in some extremely acidic conditions, for instance, Helicobacter pylori (H. pylori) in a stomach . Also, bacterial infections may induce an acidic microenvironment as a result of their metabolic activities or the resulting immune response .…”

“…The conventional α‐helical AMPs may lead to adverse peptide interactions with plasma proteins and suffer from a fast clearance from the bloodstream . To balance the bioaccessibility and bactericidal efficacy, Cheng and Xiong et al developed a series of secondary structure transitionable polypeptides for infection control . A class of pH‐sensitive, helix–coil conformation transitionable antimicrobial polypeptides (HCT‐AMPs) were developed, which bear randomly presented anionic carboxyl groups and cationic poly(γ‐6‐ N ‐(methyldihexylammonium)hexyl‐ l ‐glutamate) (PHLG‐MHH) residues.…”

“…The HCT‐AMPs showed negligible bactericidal effect at physiological pH, where they are randomly presented. Triggered by the low pH in stomach, the polypeptides change to their helical structures, which exhibited enhanced bactericidal effect against the pathogenic H. pylori ( Figure 2 A) . Similarly, the overexpressed bacterial enzymes are also able to trigger the secondary structure transition.…”

“…A) Schematic illustration of the pH‐responsive conformation transition of HCT‐AMP(PGA)‐r‐(PHLG‐MHH). Reproduced with permission . Copyright 2017, National Academy of Sciences.…”