Antisense PNA accumulates in Escherichia coli and mediates a long post-antibiotic effect

Abbas Nikravesh, Rikard Dryselius, Omid R Faridani, Shan Goh, Majid Sadeghizadeh, Mehrdad Behmanesh, Anita Ganyu, Erik Jan Klok, Rula Zain, Liam Good

Research output: Contribution to journalArticlepeer-review

46 Citations (Scopus)
14 Downloads (Pure)

Abstract

Antisense agents that target growth-essential genes display surprisingly potent bactericidal properties. In particular, peptide nucleic acid (PNA) and phosphorodiamidate morpholino oligomers linked to cationic carrier peptides are effective in time kill assays and as inhibitors of bacterial peritonitis in mice. It is unclear how these relatively large antimicrobials overcome stringent bacterial barriers and mediate killing. Here we determined the transit kinetics of peptide-PNAs and observed an accumulation of cell-associated PNA in Escherichia coli and slow efflux. An inhibitor of drug efflux pumps did not alter peptide-PNA potency, indicating a lack of active efflux from cells. Consistent with cell retention, the post-antibiotic effect (PAE) of the anti-acyl carrier protein (acpP) peptide-PNA was greater than 11 hours. Bacterial cell accumulation and a long PAE are properties of significant interest for antimicrobial development.

Original languageEnglish
Pages (from-to)1537-42
Number of pages6
JournalMolecular therapy : the journal of the American Society of Gene Therapy
Volume15
Issue number8
DOIs
Publication statusPublished - 1 Aug 2007

Keywords

  • Acyl Carrier Protein
  • Anti-Bacterial Agents
  • Base Sequence
  • DNA, Antisense
  • Dipeptides
  • Escherichia coli
  • Kinetics
  • Microbial Viability
  • Peptide Nucleic Acids
  • Journal Article
  • Research Support, Non-U.S. Gov't

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