Antisense PNA accumulates in Escherichia coli and mediates a long post-antibiotic effect.
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.
Nikravesh
Abbas
A
Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
Dryselius
Rikard
R
Faridani
Omid R
OR
Goh
Shan
S
Sadeghizadeh
Majid
M
Behmanesh
Mehrdad
M
Ganyu
Anita
A
Klok
Erik Jan
EJ
Zain
Rula
R
Good
Liam
L
D000213:Acyl Carrier Protein / Q000235:genetics / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001483:Base Sequence; D016373:DNA, Antisense / Q000235:genetics*; D004151:Dipeptides / Q000494:pharmacology; D004926:Escherichia coli / Q000166:cytology / Q000187:drug effects* / Q000235:genetics* / Q000378:metabolism; D007700:Kinetics; D050296:Microbial Viability; D020135:Peptide Nucleic Acids / Q000235:genetics*
D000213:Acyl Carrier Protein; D000900:Anti-Bacterial Agents; D016373:DNA, Antisense; D004151:Dipeptides; D020135:Peptide Nucleic Acids; C474925:phenylalanylarginine-naphthylamide