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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.


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.


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.


Vingsbo Lundberg C.,Statens Serum Institute | Vaara T.,Northern Antibiotics Ltd | Frimodt-Moller N.,Statens Serum Institute | Vaara M.,Northern Antibiotics Ltd | Vaara M.,University of Helsinki
Journal of Antimicrobial Chemotherapy | Year: 2010

Objectives: Novel synthetic polymyxin derivatives including NAB737 and NAB739 are as effective as polymyxin B in vitro against the common opportunistic pathogen Escherichia coli. Another derivative, NAB7061, lacks direct antibacterial action but sensitizes E. coli to several other antibacterial agents including macrolides. The renal handling of NAB739 and NAB7061 in rats differs from that of polymyxin B. Furthermore, the affinities of NAB739 and NAB7061 for isolated rat kidney brush border membrane are significantly lower than that of polymyxin B. Here we investigate the in vivo antibacterial effect of these compounds. Methods: The polymyxin derivatives were evaluated in an experimental murine peritonitis model. Immunocompetent mice were infected intraperitoneally with E. coli IH3080 and were subcutaneously treated with NAB737, NAB739 or NAB7061. Results: A >4.0 log. 10 reduction in bacterial load compared with saline control was achieved 6 h after initiation of treatment with 1 mg/kg of NAB739 twice or 4 mg/kg of NAB737 twice. Combination therapy with NAB7061 (5 mg/kg) twice and erythromycin (10 mg/kg) resulted during the same time course in a >2.0 log. 10 reduction in bacterial load compared with saline control. Neither NAB7061 nor erythromycin was effective as monotherapy. Together with the ability to reduce bacterial load, the NAB compounds also improved the clinical status of the mice. Conclusions: We found that the three novel synthetic polymyxin B derivatives had a potent in vivo bactericidal effect against E. coli. © The Author 2010. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.


Vaara M.,Northern Antibiotics Ltd | Vaara M.,University of Helsinki | Sader H.S.,JMI Laboratories | Rhomberg P.R.,JMI Laboratories | And 2 more authors.
Journal of Antimicrobial Chemotherapy | Year: 2013

Objectives: In spite of reported nephrotoxicity, polymyxins have been reinstated as the last-line therapy to treat infections caused by Gram-negative bacterial strains that are resistant to other agents. NAB739 has a cyclic portion identical to that of polymyxin B, but its linear peptide portion consists of threonyl-. d-serinyl instead of diaminobutyryl-threonyl-diaminobutyryl. Therefore, NAB739 lacks both of the positive charges present in the linear part of polymyxin B. Here, we compare the antibacterial activity of NAB739 with that of polymyxin B against a representative collection of contemporary Gram-negative bacteria. Methods: NAB739 and polymyxin B MIC values were determined for 310 clinical isolates by the reference broth microdilution method according to CLSI document M07-A9 (2012). Results: MIC90s of NAB739 for the subset consisting of polymyxin-susceptible (MIC, ≤2 mg/L) clinical isolates of Escherichia coli (n = 51), Klebsiella pneumoniae (n = 50), Acinetobacter spp. (n = 49) and Pseudomonas aeruginosa (n = 49) were 2, 2, 8 and 16 mg/L, respectively. For polymyxin-non-susceptible strains of E. coli (n = 12), K. pneumoniae (n = 11), Acinetobacter spp. (n = 11) and P. aeruginosa (n = 14) the NAB739 MIC90 was ≥64 mg/L. Conclusions: The MIC90 of NAB739 for polymyxin-susceptible strains of E. coli and K. pneumoniae was identical to and 2-fold higher than that of polymyxin B, respectively. For polymyxin-susceptible strains of Acinetobacter spp. and P. aeruginosa, the MIC90 of NAB739 was 4-fold and 8-fold higher than that of polymyxin B, respectively. For polymyxin-non-susceptible strains of all these species, the MIC90 values of NAB739 were high and 2- to 4-fold higher than those of polymyxin B. © The Author 2012. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.


Vaara M.,Northern Antibiotics Ltd | Vaara M.,University of Helsinki | Siikanen O.,Alimetrics Ltd | Apajalahti J.,Alimetrics Ltd | And 2 more authors.
Journal of Antimicrobial Chemotherapy | Year: 2010

Objectives: To determine the susceptibility of carbapenemase-producing strains of Klebsiella pneumoniae and Escherichia coli to the direct antibacterial activity of NAB739 and to the synergistic activity of NAB7061 with rifampicin and clarithromycin. NAB739 and NAB7061 are novel polymyxin derivatives that lack the cationic charges in the linear peptide portion of polymyxin B and have pharmacokinetic properties different from those of polymyxin B. Methods: MIC determinations were performed by the agar dilution method using CLSI guidelines. Polymyxin B was used as a comparison. Synergism studies measured fractional inhibitory concentration indices (FICIs) by using increasing concentrations of the compounds in Mueller-Hinton agar and Etests™. Results: The MICs of NAB739 for all nine polymyxin-susceptible, carbapenemase-producing strains were identical or very close to those determined for E. coli ATCC 25922, for K. pneumoniae ATCC 13883, as well as for 18 clinical carbapenem-susceptible isolates. At a concentration of 4 mg/L, NAB7061 decreased the MIC of rifampicin and clarithromycin for all carbapenemase strains by factors ranging from 6 to 500. The polymyxin-resistant strain K. pneumoniae CL5762B was sensitized by a factor of 24 to rifampicin (FICI, 0.167) and by a factor of 12 to clarithromycin (FICI, 0.208). Conclusions: Polymyxin-susceptible, carbapenemase-producing strains are as susceptible to NAB739 as are the carbapenem-susceptible clinical isolates. In addition, NAB7061 has notable synergism with rifampicin and clarithromycin against all the carbapenemase-producing strains tested, including the polymyxin-resistant K. pneumoniae strain. © The Author 2010. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.


Vaara M.,Northern Antibiotics Ltd. | Vaara M.,University of Helsinki | Vaara T.,Northern Antibiotics Ltd.
Peptides | Year: 2010

Polymyxin B and colistin are pentacationic lipopeptides that possess a cyclic heptapeptide portion, a linear tripeptide portion, and a fatty acyl tail. They are used, in spite of nephrotoxicity, to treat infections caused by extremely multiresistant Gram-negative bacteria. We have recently developed novel derivatives, that carry three cationic charges only. Some of them, including NAB739, are directly antibacterial whereas others, including NAB7061, lack the direct activity but sensitize bacteria to other antibiotics. NAB739 and NAB7061 differ from the old polymyxins in their renal handling and have reduced affinity to kidney brush border membrane. To further study the structure-activity relationships, we here synthesized eight additional derivatives and tested their antibacterial activity. NAB751 carries methylheptanoyl as the fatty acyl instead of octanoyl in NAB739 and was as active as NAB739, whereas NAB750 with dodecanoyl was less active. NAB781 and NAB782 with the linear peptide portion Ser-DSer and Ser-Ser-DSer, respectively, were less active than NAB739 that carries Thr-DSer. NAB771 with Thr at position 8 in the cyclic portion (instead of Dab in NAB7061) and Thr-Dab as the linear peptide portion (instead of Thr-Abu in NAB7061), resembled NAB7061 in its activity. However, replacement of two Dab residues in the cyclic portion with Thr greatly decreased the activity, even though the loss of the cationic charges was compensated by introducing two Dab residues in the linear portion. These findings reveal that subtle structural modifications have a major effect on the antibacterial activity and that it is possible to design numerous tricationic polymyxin derivatives that are antibacterial. © 2010 Elsevier Inc. All rights reserved.


Patent
Northern Antibiotics Ltd. | Date: 2012-12-10

The present invention relates to a polymyxin derivative and to a combination product comprising at least two such derivatives. The invention further relates to a method for treating, alleviating or ameliorating an infection in a subject caused by a Gram-negative bacterium, by administering a therapeutically effective amount of a derivative according to the present invention to said subject; to a method for sensitizing Gram-negative bacteria to an antibacterial agent by administering, simultaneously or sequentially in any order a therapeutically effective amount of said antibacterial agent and a derivative according to the present invention to said subject; to methods for developing novel antibiotics; for reducing the nephrotoxicity, for improving the pharmacokinetic properties of natural polymyxins and octapeptins; and for sensitizing clinically important bacteria to a host defense mechanism complement present in serum. Finally, the invention relates to a process for preparing such polymyxin derivatives.


Patent
Northern Antibiotics Ltd. | Date: 2016-01-19

The present invention relates to a polymyxin derivative of formula (I)


Patent
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.

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