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

  1. Jianjun Chenga,c,d,g,h,i,j,2
  1. aDepartment of Materials Science and Engineering, University of Illinois at Urbana–Champaign, Urbana, IL 61801;
  2. bDepartment of Biochemistry, University of Illinois at Urbana–Champaign, Urbana, IL 61801;
  3. cJiangsu 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;
  4. dFrederick Seitz Materials Research Laboratory, University of Illinois at Urbana–Champaign, Urbana, IL 61801;
  5. eSun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangdong, China 510120;
  6. fDivision of Gastroenterology, Department of Medicine and Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN 37232;
  7. gDepartment of Bioengineering, University of Illinois at Urbana–Champaign, Urbana, IL 61801;
  8. hBeckman Institute for Advanced Science and Technology, University of Illinois at Urbana–Champaign, Urbana, IL 61801;
  9. iDepartment of Chemistry, University of Illinois at Urbana–Champaign, Urbana, IL 61801;
  10. jCarl R. Woese Institute for Genomic Biology, University of Illinois at Urbana–Champaign, Urbana, IL 61801
  1. Edited by Alexander M. Klibanov, Massachusetts Institute of Technology, Cambridge, MA, and approved October 20, 2017 (received for review June 9, 2017)

Significance

Clinical treatment of Helicobacter pylori using combination therapy is greatly challenged by the undesired killing of commensal bacteria and progressive development of drug resistance. To address these issues, we developed pH-sensitive, helix–coil conformation transitionable, antimicrobial polypeptides as a single therapeutic agent to selectively kill H. pylori under acidic condition in the stomach with minimal toxicity to commensal bacteria and diminished drug resistance. Through the control of the secondary structure transition, the polypeptides showed unappreciable toxicity to commensal bacteria and tissues at physiological pH when they adopted random coiled conformation, while the restoration of helical structure in the acidic stomach allowed the polypeptide to regain membrane disruptive capability to effectively and selectively kill H. pylori, including drug-resistant strains.

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 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.

Footnotes

  • ?1M.X., Y.B., and X.X. contributed equally to this work.

  • ?2To whom correspondence may be addressed. Email: lcyin{at}suda.edu.cn, lfchen{at}life.illinois.edu, or jianjunc{at}illinois.edu.
  • Author contributions: M.X., Y.B., L.Y., L.-F.C., and J. Cheng designed research; M.X., Y.B., X.X., H.W., Z.H., Z.W., Z.S., and J. Chen performed research; M.X., Y.B., X.X., Y.L., S.H., R.M.P., L.Y., L.-F.C., and J. Cheng analyzed data; and M.X., Y.B., L.Y., L.-F.C., and J. Cheng wrote the paper.

  • The authors declare no conflict of interest.

  • This article is a PNAS Direct Submission.

  • This article contains supporting information online at www.danielhellerman.com/lookup/suppl/doi:10.1073/pnas.1710408114/-/DCSupplemental.

Published under the PNAS license.

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