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Two distinct amphipathic peptide antibiotics with systemic efficacy.

Jayaram Lakshmaiah Narayana1, Biswajit Mishra1, Tamara Lushnikova1

  • 1Department of Pathology and Microbiology, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198-5900.

Proceedings of the National Academy of Sciences of the United States of America
|July 30, 2020
PubMed
Summary

Two novel antimicrobial peptides, horine and verine, demonstrate potent systemic efficacy against drug-resistant pathogens and biofilms in mice, with no observed nephrotoxicity, paving the way for new antibiotic development.

Keywords:
NMRantibiotic resistancenephrotoxicitypeptide antibioticssystemic efficacy

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Area of Science:

  • Biochemistry
  • Microbiology
  • Pharmacology

Background:

  • Antimicrobial peptides (AMPs) show promise against antibiotic-resistant pathogens.
  • Current AMP research primarily targets topical applications, lacking systemic efficacy strategies.
  • Designing AMPs for systemic use requires novel approaches to membrane interaction and structure.

Purpose of the Study:

  • To design and characterize novel AMPs with systemic efficacy.
  • To investigate the structure-activity relationship of AMPs with distinct membrane orientations.
  • To evaluate the therapeutic potential of these AMPs against resistant infections and biofilms.

Main Methods:

  • Database-guided discovery and structure-based design of two AMPs with identical amino acid composition.
  • Solid-state 15N NMR to determine peptide orientation (horizontal helix - horine, vertical spiral - verine) on membranes.
  • In vivo efficacy studies in murine models against Gram-positive and broad-spectrum pathogens.
  • Assessment of biofilm eradication and systemic toxicity (nephrotoxicity).

Main Results:

  • Two peptides, horine and verine, adopted distinct membrane-bound structures (horine: horizontal helix, verine: vertical spiral).
  • Verine exhibited broad-spectrum activity, while horine was potent against Gram-positive bacteria.
  • Both peptides showed significant systemic efficacy in mice, protecting >80% from lethal infections.
  • Peptides effectively eliminated resistant pathogens and biofilms without causing nephrotoxicity.

Conclusions:

  • Horine and verine represent a significant advancement in AMP design for systemic applications.
  • The distinct structural conformations (horine and verine) correlate with differential antimicrobial spectra and efficacy.
  • These peptides offer a promising therapeutic strategy against challenging drug-resistant infections and biofilms.