P. Natl. Acad. Sci. USA: Selective Killing of Helicobacter Pylori with pH-Responsive Helix–Coil Conformation Transitionable Antimicrobial Polypeptides

Title：

Selective Killing of Helicobacter Pylori with pH-Responsive Helix–Coil Conformation Transitionable  Antimicrobial Polypeptides

Authors：

Menghua Xiong¹, Yan Bao², Xin Xu³, Hua Wang¹, Zhiyuan Han¹, Zhiyu Wang⁴, Yeqing Liu⁵, Songyin Huang⁵, Ziyuan Song¹, Jinjing Chen², Richard M. Peek Jr.⁶, Lichen Yin³, Lin-Feng Chen², and Jianjun Cheng^{1,3,4,7,8,9,10}

Institutions：

¹Department of Materials Science and Engineering, University of Illinois at Urbana–Champaign, Urbana,   IL 61801;

²Department of Biochemistry, University of Illinois at Urbana–Champaign, Urbana, IL 61801;

³Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Institute of Functional Nano & Soft Materials, Collaborative Innovation Center of Suzhou Nano Science & Technology, Soochow University, Jiangsu, China 215123;

⁴Frederick Seitz Materials Research Laboratory, University of Illinois at Urbana–Champaign, Urbana, IL 61801;

⁵Sun Yat-sen Memorial   Hospital, Sun Yat-sen University, Guangdong, China 510120;

⁶Division of Gastroenterology, Department of Medicine and Cancer Biology, Vanderbilt   University School of Medicine, Nashville, TN 37232;

⁷Department of Bioengineering, University of Illinois at Urbana–Champaign, Urbana, IL 61801;   

⁸Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana–Champaign, Urbana, IL 61801;

⁹Department of Chemistry, University of Illinois at Urbana–Champaign, Urbana, IL 61801;

¹⁰Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana–Champaign, Urbana, IL 61801

Abstract：

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 tripletherapy 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.

IF：

9.661

Link：

http://www.pnas.org/content/114/48/12675

Editor: Danting Xiang