title: Neopeptide antibiotics that function as opsonins and membrane-permeabilizing agents for gram-negative bacteria.
abstract: 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.
authors.affiliation: Department of Human Microbiology, Sackler Faculty of Medicine, Tel Aviv University, Tel-Aviv 69978, Israel.
authors.forename: Haim
authors.initials: H
authors.lastname: Tsubery
authors.forename: Hertzig
authors.initials: H
authors.lastname: Yaakov
authors.forename: Sofia
authors.initials: S
authors.lastname: Cohen
authors.forename: Tal
authors.initials: T
authors.lastname: Giterman
authors.forename: Ariella
authors.initials: A
authors.lastname: Matityahou
authors.forename: Mati
authors.initials: M
authors.lastname: Fridkin
authors.forename: Itzhak
authors.initials: I
authors.lastname: Ofek
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016470:Bacteremia / Q000188:drug therapy / Q000382:microbiology; D001769:Blood / Q000382:microbiology; D002463:Cell Membrane Permeability / Q000187:drug effects*; D002633:Chemotaxis; D003091:Colistin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D024881:Drug Resistance, Bacterial; D004917:Erythromycin / Q000008:administration & dosage / Q000494:pharmacology; D006090:Gram-Negative Bacteria / Q000187:drug effects*; D006801:Humans; D007710:Klebsiella Infections / Q000188:drug therapy / Q000382:microbiology; D007711:Klebsiella pneumoniae / Q000187:drug effects; D017737:Macrophages, Peritoneal / Q000276:immunology; D051379:Mice; D008826:Microbial Sensitivity Tests; D009895:Opsonin Proteins / Q000378:metabolism*; D010455:Peptides / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011112:Polymyxin B / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D009895:Opsonin Proteins; D010455:Peptides; D004917:Erythromycin; C038934:polymyxin B nonapeptide; D011112:Polymyxin B; D003091:Colistin