86408-36-8Relevant articles and documents
Structure - Function studies of Polymyxin B nonapeptide: Implications to sensitization of Gram-negative bacteria
Tsubery,Ofek,Cohen,Fridkin
, p. 3085 - 3092 (2000)
Polymyxin B nonapeptide (PMBN), a cationic cyclic peptide derived by enzymatic processing from the naturally occurring peptide polymyxin B, is able to increase the permeability of the outer membrane of Gram-negative bacteria toward hydrophobic antibiotics probably by binding to the bacterial lipopolysaccharide (LPS). We have synthesized 11 cyclic analogues of PMBN and evaluated their activities compared to that of PMBN. The synthetic peptides were much less potent than PMBN in their capacity to sensitize Escherichia coli and Klebsiella pneumoniae toward novobiocin and to displace dansyl-PMBN from Escherichia coli LPS. Moreover, unlike PMBN, none of the analogues were able to inhibit the growth of Pseudomonas aeruginosa. The structural - functional features of PMBN were characterized and identified with regard to the ring size, the distance between positive charges and peptide backbone, the chirality of the DPhe-Leu domain, and the nature of the charged groups. Apparently, the structure of PMBN is highly specific for efficient perturbation of the outer membrane of Gram-negative bacteria as well as for LPS binding. The present study further increases our understanding of the complex PMBN-LPS and may, potentially, enable the design of compounds having enhanced permeabilization potency of the Gram-negative outer membrane.
Neopeptide antibiotics that function as opsonins and membrane- permeabilizing agents for gram-negative bacteria
Tsubery, Haim,Yaakov, Hertzig,Cohen, Sofia,Giterman, Tal,Matityahou, Ariella,Fridkin, Mati,Ofek, Itzhak
, p. 3122 - 3128 (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. Copyright
Chemical conversion of natural polymyxin B and colistin to their N-terminal derivatives
Okimura, Keiko,Ohki, Kazuhiro,Sato, Yuki,Ohnishi, Kuniharu,Uchida, Yoshiki,Sakura, Naoki
, p. 543 - 552 (2008/09/18)
The chemical conversions of natural polymyxin B and colistin, which are fatty-acylated cyclic decapeptides, to polymyxin (2-10) and colistin (2-10) derivatives were examined. The Nα-free and side chain N γ-protected nonapeptides, i.e., tetrakis(Nγ- trifluoroacetyl)-polymyxin B (2-10) and tetrakis(Nγ- trifluoroacetyl)-colistin (2-10), were prepared by trifluoroacetylation of polymyxin B and colistin, followed by chemical cleavage with 50% methanesulfonic acid to remove Nα-alkanoyl-Nγ- trifluoroacetyl-Dab-OH. The Nγ-protected nonapeptides were useful starting materials for the semi-synthesis of N-terminal derivatives by selective Nα-acylation at Thr2, followed by the removal of the Nγ-trifluoroacetyl protecting group with aqueous piperidine. Further, myristoyl-polymyxin B (2-10) and myristoyl-colistin (2-10) retained their antimicrobial activity with an MIC of 2-4 nmol mL-1 against Escherichia coli, Salmonella Typhimurium, and Pseudomonas aeruginosa. They also retained their high lipopolysaccahride (LPS) binding activity. Acetyl-polymyxin B (2-10) and acetyl-colistin (2-10) exhibited very low biological activities, except for a high bactericidal activity specifically against Pseudomonas aeruginosa with an MIC of 2 nmol mL-1. The distinct sensitivity of three Gram-negative bacteria tested toward acetyl-nonapeptides suggested that the N-terminal hydrophobic character of the fatty-acylated polymyxin peptides was necessary for the bactericidal activity against Escherichia coli and Salmonella Typhimurium, but not against Pseudomonas aeruginosa.
