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Vaara M.,University of Helsinki | Vaara M.,Northern Antibiotics Ltd.
Journal of Antimicrobial Chemotherapy | Year: 2013

BPolymyxin B and colistin (polymyxin E) are bactericidal pentacationic lipopeptides that act specifically on Gramnegative bacteria, first by disrupting their outermost permeability barrier, the outer membrane (OM), and then damaging the cytoplasmic membrane. Both were discovered in the mid-1950s and subsequently used in intravenous therapy, but soon largely abandoned because of nephrotoxicity. The emergence of extremely multiresistant strains has now forced clinicians to reinstate them in the therapy of severe infections caused by such strains. This article reviews recent attempts to develop novel derivatives of polymyxins that exhibit less toxicity and greater potency than the existing drugs. In addition, studies of novel des-fatty acyl-polymyxin derivatives that display activity against Pseudomonas aeruginosa are included. The review also covers recent studies of derivatives that lack potent bactericidal action, but which disrupt the OM, which increases bacterial permeability to other antibiotics, facilitating their entry into the cell © The Author 2013.

Vaara M.,Northern Antibiotics Ltd. | Vaara M.,University of Helsinki
Current Opinion in Microbiology | Year: 2010

The emerging very multiresistant Gram-negative bacteria cause remarkable therapeutic challenges. There are no novel classes of agents in clinical development for the treatment of Gram-negative infections. Polymyxins (polymyxin B and colistin) were abandoned in the seventies but are now back in the therapy as the last resort. Their nephrotoxicity may complicate the therapy or even necessitate its discontinuation. Less toxic polymyxin derivatives would be highly welcome. Novel derivatives lack in strategic positions two of the five cationic charges of polymyxins, differ from polymyxins in their renal handling and affinity to kidney brush-border membrane, and are in preclinical studies. Less characterized other recent derivatives, also reviewed here, have increased the collective knowledge on the structure-function relationships in polymyxins. Acquired resistance to polymyxins has been encountered. However, the resistance mechanism compromises the function of the bacterial outer membrane as a permeability barrier to other noxious agents. © 2010 Elsevier Ltd.

Northern Antibiotics Ltd. | Date: 2013-12-23

The present invention relates to a polymyxin derivative wherein the derivative has a total of three positive charges at physiological pH and wherein the terminal moiety (D) of the derivative comprises a total of 1 to 5 carbon atoms. The invention also relates to a method of treating a subject for a gram-negative bacterial infection by administering a polymyxin derivative of the invention in combination with a second antibacterial agent. Finally, the invention relates to a process for preparing such polymyxin derivatives.

Vaara M.,Northern Antibiotics Ltd. | Vaara M.,University of Helsinki | Siikanen O.,Alimetrics Ltd. | Apajalahti J.,Alimetrics Ltd. | And 7 more authors.
Antimicrobial Agents and Chemotherapy | Year: 2010

Polymyxins are cationic lipopeptides (five cationic charges) and the last resort for the treatment of serious Gram-negative infections caused by multiresistant strains. NAB741 has a cyclic peptide portion identical to that of polymyxin B but carries in the linear peptide portion a threonyl-D-serinyl residue (no cationic charges) instead of the diaminobutyryl-threonyl- diaminobutyryl residue (two cationic charges). At the N terminus of the peptide, NAB741 carries an acetyl group instead of a mixture of methyl octanoyl and methyl heptanoyl residues. NAB741 sensitized Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, and Acinetobacter baumannii to antibiotics against which the intact outer membrane is an effective permeability barrier. When tested by using Etest strips on plates containing increasing concentrations of NAB741, the fractional inhibition concentration index (FICI) of the combination of NAB741 with rifampin ranged from ≤0.111 to 0.158 and that with clarithromycin from ≤0.094 to 0.292. When tested by the checkerboard method, the corresponding FICI values against E. coli ATCC 25922 were ≤0.141 to ≤0.155 with rifampin and 0.094 with clarithromycin. In addition, at 4 μg/ml, NAB741 decreased the MICs of azithromycin, mupirocin, fusidic acid, and vancomycin for E. coli strains and E. cloacae by factors ranging from 8 to 200. A sister peptide, NAB752, carrying a threonyl-aminobutyryl residue as the linear peptide portion, was inactive. Furthermore, NAB741 sensitized E. coli to the bactericidal activity of fresh guinea pig serum. The renal clearance of NAB741 was approximately 400-fold, 16-fold, and 8-fold higher than those measured for colistin, NAB7061, and NAB739, respectively. Copyright © 2010, American Society for Microbiology. All Rights Reserved.

Mingeot-Leclercq M.-P.,Catholic University of Louvain | Tulkens P.M.,Catholic University of Louvain | Denamur S.,Catholic University of Louvain | Vaara T.,Northern Antibiotics Ltd. | And 2 more authors.
Peptides | Year: 2012

The emergence of very multiresistant Gram-negative bacterial strains has reinstated polymyxins (polymyxin B, colistin), pentacationic lipopeptides, in the therapy, in spite of their nephrotoxicity. Extensive tubular reabsorption concentrates polymyxin in proximal tubular cells. The novel polymyxin derivatives NAB739, NAB7061 and NAB741 have their cyclic part identical to that of polymyxin B, but their side chain consists of uncharged octanoyl-threonyl-d- serinyl, octanoyl-threonyl-aminobutyryl, and acetyl-threonyl-d-serinyl respectively. In this study, we compared the toxicities of NAB739, NAB7061 and NAB741 with that of polymyxin B by using the porcine renal proximal tubular cell line LLC-PK1 electroporated or incubated with the selected compound. Both the ability to cause cell necrosis (quantified as the leakage of lactate dehydrogenase) and the ability to cause apoptosis (as quantified by counting apoptotic nuclei) were assessed. In electroporated cells, polymyxin B induced total (>85%) necrosis of the cells at 0.016 mM, whereas an approx. 8-fold concentration of NAB739 and NAB7961 and an approx. 32-fold concentration of NAB741 was required for the same effect. In cells treated without electroporation (incubated), polymyxin B elicited a marked degree (approx. 50%) of necrosis at 0.5 mM, whereas the NAB compounds were inert even at 1 mM. Neither polymyxin B nor the NAB compounds induced apoptosis. © 2012 Elsevier Inc. All rights reserved.

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