De Novo Designed Hexadecapeptides Synergize Glycopeptide Antibiotics Vancomycin and Teicoplanin against Pathogenic Klebsiella pneumoniae via Disruption of Cell Permeability and Potential

Ping Zeng, Chen Xu, Chenyu Liu, Jun Liu, Qipeng Cheng, Wei Gao, Xuemei Yang, Sheng Chen, Kin Fai Chan (Corresponding Author), Kwok Yin Wong (Corresponding Author)

Research output: Journal article publicationJournal articleAcademic researchpeer-review

2 Citations (Scopus)

Abstract

Given the worldwide prevalence of pathogenic drug-resistant bacteria and the slow pace of new antibacterial development, discovering new uses for approved drugs that are outside the scope of the original indication is increasingly becoming an attractive proposition. In this work, seven linear cationic hexadecapeptides were designed, synthesized, and characterized. These amphiphilic peptides are able to transform from the random coil structure in water to α-helix in SDS solution and have only modest bioactivity to limited bacterial strains when used alone. Surprisingly, one of them, namely, zp16, was found to demonstrate significant synergy with vancomycin and teicoplanin against highly pathogenic Klebsiella pneumoniae (KP) with FIC index as low as 0.03. Checkerboard assay indicated that, in the presence of 8 μM zp16, the minimum inhibitory concentration (MIC) of vancomycin greatly was reduced from >128 to 1 μM to clinically isolated carbapenem-resistant KP94. Additionally, the vancomycin-zp16 combination exhibited neglectable toxicity in vitro and in vivo. Further efficacy studies confirmed that the survival rate of a combination therapy at 100 mg/kg of zp16 and vancomycin was 30% higher than that of the single-drug treatment. More importantly, drug resistance has not developed to the combination even at the 20th serial passage of KP1088. Mechanistic studies revealed that zp16 could strengthen the vancomycin's influence on cell permeability and potential, leading to markedly reduced biofilm formation and rapid bactericidal effect. This new combination strategy expands the antibacterial spectrum of glycopeptide antibiotics and opens a new research direction for their application to treat pathogenic KP infection.

Original languageEnglish
Pages (from-to)1738-1752
Number of pages15
JournalACS Applied Bio Materials
Volume3
Issue number3
DOIs
Publication statusPublished - 16 Mar 2020

Keywords

  • cationic peptides
  • cell selectivity
  • Klebsiella pneumoniae
  • membrane permeability
  • membrane potential
  • vancomycin adjuvant

ASJC Scopus subject areas

  • Biomaterials
  • Chemistry(all)
  • Biomedical Engineering
  • Biochemistry, medical

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