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Antimicrobial Agents and Chemotherapy, August 2005, p. 3203-3207, Vol. 49, No. 8
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.8.3203-3207.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Peptide Nucleic Acid Antisense Oligomer as a Therapeutic Strategy against Bacterial Infection: Proof of Principle Using Mouse Intraperitoneal Infection

Xin-Xing Tan,1* Jeffrey K. Actor,2 and Yin Chen1

Cytogenix, Inc., 3100 Wilcrest Dr., Suite 140, Houston, Texas 77042,1 Department of Pathology and Laboratory Medicine, University of Texas Medical School, 6431 Fannin St., Houston, Texas 770302

Received 16 February 2005/ Returned for modification 17 April 2005/ Accepted 14 May 2005

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-1ß (IL-1ß), 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.

* Corresponding author. Mailing address: Cytogenix, Inc., 3100 Wilcrest Drive, Suite 140, Houston, TX 77042. Phone: (713) 789-0070. Fax: (713) 789-0702. E-mail: xxtan{at}cytogenix.com.

Antimicrobial Agents and Chemotherapy, August 2005, p. 3203-3207, Vol. 49, No. 8
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.8.3203-3207.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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