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

doi:10.1038/sj.mt.6300209

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 journal › Article › peer-review

46 Citations (Scopus)

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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 language	English
Pages (from-to)	1537-42
Number of pages	6
Journal	Molecular therapy : the journal of the American Society of Gene Therapy
Volume	15
Issue number	8
DOIs	https://doi.org/10.1038/sj.mt.6300209
Publication status	Published - 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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1-s2.0-S1525001616324492-mainFinal published version, 493 KBLicence: CC BY

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title = "Antisense PNA accumulates in Escherichia coli and mediates a long post-antibiotic effect",

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.",

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author = "Abbas Nikravesh and Rikard Dryselius and Faridani, {Omid R} and Shan Goh and Majid Sadeghizadeh and Mehrdad Behmanesh and Anita Ganyu and Klok, {Erik Jan} and Rula Zain and Liam Good",

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AU - Nikravesh, Abbas

AU - Dryselius, Rikard

AU - Faridani, Omid R

AU - Goh, Shan

AU - Sadeghizadeh, Majid

AU - Behmanesh, Mehrdad

AU - Ganyu, Anita

AU - Klok, Erik Jan

AU - Zain, Rula

AU - Good, Liam

PY - 2007/8/1

Y1 - 2007/8/1

N2 - 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.

AB - 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.

KW - Acyl Carrier Protein

KW - Anti-Bacterial Agents

KW - Base Sequence

KW - DNA, Antisense

KW - Dipeptides

KW - Escherichia coli

KW - Kinetics

KW - Microbial Viability

KW - Peptide Nucleic Acids

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1038/sj.mt.6300209

DO - 10.1038/sj.mt.6300209

M3 - Article

C2 - 17534267

SN - 1525-0016

VL - 15

SP - 1537

EP - 1542

JO - Molecular therapy : the journal of the American Society of Gene Therapy

JF - Molecular therapy : the journal of the American Society of Gene Therapy

IS - 8

ER -

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

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Keywords

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