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Antimicrobial Agents and Chemotherapy, August 2005, p. 3122-3128, Vol. 49, No. 8
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.8.3122-3128.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Neopeptide Antibiotics That Function as Opsonins and Membrane-Permeabilizing Agents for Gram-Negative Bacteria

Haim Tsubery,1,2 Hertzig Yaakov,1 Sofia Cohen,1 Tal Giterman,1 Ariella Matityahou,1 Mati Fridkin,2 and Itzhak Ofek1*

Department of Human Microbiology, Sackler Faculty of Medicine, Tel Aviv University, Tel-Aviv 69978, Israel,1 Department of Organic Chemistry, The Weizmann Institute of Science, Rehovot 76100, Israel2

Received 22 February 2005/ Returned for modification 18 March 2005/ Accepted 18 April 2005

We suggest a novel approach to enhancing antimicrobial drug action by utilizing engineered peptide conjugates. Our most potent conjugates, [fMLF]PMBN and [fMLF]PMEN, are nonapeptides derived from polymyxin B's (PMB's) cyclic moiety (Thr-Dab-cyclo[Dab-Dab-D-Phe-Leu-Dab-Dab-Thr], where Dab is 2,4-diaminobutyric acid) and polymyxin E's (PME's) cyclic moiety (Thr-Dab-cyclo[Dab-Dab-D-Leu-Leu-Dab-Dab-Thr]), respectively, attached to a linear tail comprised of formyl-Met-Leu-Phe (fMLF). The cyclic part binds to gram-negative lipopolysaccharides, rendering the bacterial outer membrane permeable to hydrophobic antibiotics. The tail confers chemotactic and opsonic activities upon the conjugates. These two activities appear to be the basis for the conjugates' antibacterial activities. The conjugates are 8 to 10 times less toxic than the parent PMB or PME antibiotics. Fourteen of 18 mice lethally challenged with erythromycin-resistant Klebsiella pneumoniae survived following intraperitoneal administration of erythromycin and [fMLF]PMBN, whereas erythromycin or the peptide conjugate alone had no effect. Moreover, the clearance of Klebsiella from blood was markedly enhanced by intravenous injection of the [fMLF]PMEN peptide conjugate compared to the clearance of the organism from the mice treated with buffer alone as a control and was similar to that achieved by the PME antibiotic. Blood clearance was also significantly enhanced by administration of PMEN either alone or in a mixture with fMLF, although the effect was less than that produced by the peptide conjugate. Since resistance to polymyxins, the parent molecules of the synthetic cyclic peptides, is rare, the emergence of bacteria resistant to the antimicrobial properties of the peptide conjugates may be precluded as well.

* Corresponding author. Mailing address: Department of Human Microbiology, Sackler Faculty of Medicine, Tel Aviv University, Tel-Aviv 69978, Israel. Phone: 972 3 640 9059. Fax: 972 3 640 9160. E-mail: aofek{at}post.tau.ac.il.

Antimicrobial Agents and Chemotherapy, August 2005, p. 3122-3128, Vol. 49, No. 8
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.8.3122-3128.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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