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Antimicrobial Agents and Chemotherapy, February 2009, p. 525-530, Vol. 53, No. 2
0066-4804/09/$08.00+0     doi:10.1128/AAC.00917-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Variations in Amino Acid Composition of Antisense Peptide-Phosphorodiamidate Morpholino Oligomer Affect Potency against Escherichia coli In Vitro and In Vivo {triangledown}

Brett L. Mellbye,1 Susan E. Puckett,2 Luke D. Tilley,1 Patrick L. Iversen,1 and Bruce L. Geller1,2*

AVI BioPharma, Inc,1 Oregon State University, Corvallis, Oregon2

Received 10 July 2008/ Returned for modification 24 September 2008/ Accepted 7 November 2008

The potency of antisense peptide-phosphorodiamidate morpholino oligomers (PPMOs) was improved by varying the peptide composition. An antisense phosphorodiamidate morpholino oligomer (PMO) complementary to the mRNA of the essential gene acpP (which encodes the acyl carrier protein required for lipid biosynthesis) in Escherichia coli was conjugated to the 5' ends of various cationic membrane-penetrating peptides. Each peptide had one of three repeating sequence motifs: C-N-N (motif 1), C-N (motif 2), or C-N-C (motif 3), where C is a cationic residue and N is a nonpolar residue. Variations in the cationic residues included arginine, lysine, and ornithine (O). Variations in the nonpolar residues included phenylalanine, valine, β-alanine (B), and 6-aminohexanoic acid (X). The MICs of the PPMOs varied from 0.625 to >80 µM (about 3 to 480 µg/ml). Three of the most potent were the (RX)6B-, (RXR)4XB-, and (RFR)4XB-AcpP PMOs, which were further tested in mice infected with E. coli. The (RXR)4XB-AcpP PMO was the most potent of the three conjugates tested in mice. The administration of 30 µg (1.5 mg/kg of body weight) (RXR)4XB-AcpP PMO at 15 min postinfection reduced CFU/ml in blood by 102 to 103 within 2 to 12 h compared to the numbers in water-treated controls. All mice treated with 30 µg/dose of (RXR)4XB-AcpP PMO survived infection, whereas all water-treated mice died 12 h postinfection. The reduction in CFU/ml in blood was proportional to the dose of PPMO from 30 to 300 µg/ml. In summary, the C-N-C motif was more effective than the other two motifs, arginine was more effective than lysine or ornithine, phenylalanine was more effective than 6-aminohexanoic acid in vitro but not necessarily in vivo, and (RXR)4XB-AcpP PMO reduced bacterial infection and promoted survival at clinically relevant doses.

* Corresponding author. Mailing address: Department of Microbiology, 220 Nash Hall, Oregon State University, Corvallis, OR 97331-3804. Phone: (541) 737-1845. Fax: (541) 737-0496. E-mail: gellerb{at}orst.edu

{triangledown} Published ahead of print on 17 November 2008.

Antimicrobial Agents and Chemotherapy, February 2009, p. 525-530, Vol. 53, No. 2
0066-4804/09/$08.00+0     doi:10.1128/AAC.00917-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Mellbye, B. L., Weller, D. D., Hassinger, J. N., Reeves, M. D., Lovejoy, C. E., Iversen, P. L., Geller, B. L. (2009). Cationic phosphorodiamidate morpholino oligomers efficiently prevent growth of Escherichia coli in vitro and in vivo. J Antimicrob Chemother 0: dkp392v1-dkp392 [Abstract] [Full Text]  
  • Mitev, G. M., Mellbye, B. L., Iversen, P. L., Geller, B. L. (2009). Inhibition of Intracellular Growth of Salmonella enterica Serovar Typhimurium in Tissue Culture by Antisense Peptide-Phosphorodiamidate Morpholino Oligomer. Antimicrob. Agents Chemother. 53: 3700-3704 [Abstract] [Full Text]  
  • Shen, N., Ko, J.-h., Xiao, G., Wesolowski, D., Shan, G., Geller, B., Izadjoo, M., Altman, S. (2009). Inactivation of expression of several genes in a variety of bacterial species by EGS technology. Proc. Natl. Acad. Sci. USA 106: 8163-8168 [Abstract] [Full Text]  


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