Two distinct amphipathic peptide antibiotics with systemic efficacy

Jayaram Lakshmaiah Narayana, Biswajit Mishra, Tamara Lushnikova, Qianhui Wu, Yashpal S. Chhonker, Yingxia Zhang, D. Zarena, Evgeniy S. Salnikov, Xiangli Dang, Fangyu Wang, Caitlin Murphy, Kirk W. Foster, Santhi Gorantla, Burkhard Bechinger, Daryl J. Murry, Guangshun Wang

Research output: Contribution to journalArticle

Abstract

Antimicrobial peptides are important candidates for developing new classes of antibiotics because of their potency against antibiotic-resistant pathogens. Current research focuses on topical applications and it is unclear how to design peptides with systemic efficacy. To address this problem, we designed two potent peptides by combining database-guided discovery with structure-based design. When bound to membranes, these two short peptides with an identical amino acid composition can adopt two distinct amphipathic structures: A classic horizontal helix (horine) and a novel vertical spiral structure (verine). Their horizontal and vertical orientations on membranes were determined by solid-state 15N NMR data. While horine was potent primarily against gram-positive pathogens, verine showed broad-spectrum antimicrobial activity. Both peptides protected greater than 80% mice from infection-caused deaths. Moreover, horine and verine also displayed significant systemic efficacy in different murine models comparable to conventional antibiotics. In addition, they could eliminate resistant pathogens and preformed biofilms. Significantly, the peptides showed no nephrotoxicity to mice after intraperitoneal or intravenous administration for 1 wk. Our study underscores the significance of horine and verine in fighting drug-resistant pathogens.

Original languageEnglish (US)
Pages (from-to)19446-19454
Number of pages9
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number32
DOIs
StatePublished - Aug 11 2020

Keywords

  • Antibiotic resistance
  • NMR
  • Nephrotoxicity
  • Peptide antibiotics
  • Systemic efficacy

ASJC Scopus subject areas

  • General

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  • Cite this

    Narayana, J. L., Mishra, B., Lushnikova, T., Wu, Q., Chhonker, Y. S., Zhang, Y., Zarena, D., Salnikov, E. S., Dang, X., Wang, F., Murphy, C., Foster, K. W., Gorantla, S., Bechinger, B., Murry, D. J., & Wang, G. (2020). Two distinct amphipathic peptide antibiotics with systemic efficacy. Proceedings of the National Academy of Sciences of the United States of America, 117(32), 19446-19454. https://doi.org/10.1073/pnas.2005540117