Peptide nucleic acid antisense oligomer as a therapeutic strategy against bacterial infection: proof of principle using mouse intraperitoneal infection.
Antisense oligodeoxynucleotides (ODNs) and their analogs have been successfully utilized to inhibit gene expression and bacterial growth in vitro or in cell culture. In this study, acpP-targeting antisense peptide nucleic acid (PNA) and its peptide conjugate were tested as potential antibacterial agents in two groups of experiments using a mouse model. In the first group, Escherichia coli mutant strain SM101 with a defective outer membrane was used to induce bacteremia and peritonitis in BALB/c mice by intraperitoneal (i.p.) injection. The resulting bacteremia was fatal within 48 h. A single i.p injection of 5 nmol (or more) of PNA administered 30 min before bacterial challenge significantly reduced the bacterial load in mouse blood. Reductions in serum concentrations of the proinflammatory cytokines tumor necrosis factor alpha, interleukin-1beta (IL-1beta), IL-6, and IL-12 were also observed. PNA treatment was effective in rescuing 100% of infected animals. In the second group, bacteremia in BALB/c mice was induced by i.p. injection of E. coli wild-type strain K-12. The infected mice were treated by a single intravenous injection of peptide-PNA conjugate 30 min after bacterial challenge. Treatment with the peptide-PNA conjugate significantly reduced the K-12 load, with modest reduction in cytokine concentrations. The conjugate treatment was also able to rescue up to 60% of infected animals. This report is the first demonstration of ODNs' antibacterial efficacy in an animal disease model. The ability of PNA and its peptide conjugate to inhibit bacterial growth and to prevent fatal infection demonstrates the potential for this new class of antibacterial agents.
Tan
Xin-Xing
XX
Cytogenix, Inc., 3100 Wilcrest Drive, Suite 140, Houston, TX 77042, USA. xxtan@cytogenix.com
Actor
Jeffrey K
JK
Chen
Yin
Y
D000213:Acyl Carrier Protein / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use*; D001059:Apoproteins / Q000235:genetics* / Q000378:metabolism; D016470:Bacteremia / Q000188:drug therapy / Q000382:microbiology / Q000401:mortality; D019281:Dimerization; D004195:Disease Models, Animal; D004926:Escherichia coli / Q000235:genetics / Q000472:pathogenicity; D004927:Escherichia coli Infections / Q000188:drug therapy / Q000382:microbiology / Q000401:mortality; D048168:Escherichia coli K12 / Q000472:pathogenicity; D029968:Escherichia coli Proteins / Q000235:genetics* / Q000378:metabolism; D054889:Fatty Acid Synthase, Type II; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use*; D020135:Peptide Nucleic Acids / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use*; D010538:Peritonitis / Q000188:drug therapy* / Q000382:microbiology / Q000401:mortality; D016896:Treatment Outcome
D000213:Acyl Carrier Protein; D000900:Anti-Bacterial Agents; D001059:Apoproteins; D029968:Escherichia coli Proteins; D016376:Oligonucleotides, Antisense; D020135:Peptide Nucleic Acids; C040157:acpP protein, E coli; D054889:Fatty Acid Synthase, Type II