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Timo Vaara - One of the best experts on this subject based on the ideXlab platform.
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Excretion of the Polymyxin Derivative NAB739 in Murine Urine
Antibiotics (Basel Switzerland), 2020Co-Authors: Martti Vaara, Timo Vaara, Janis Kuka, Eduards Sevostjanovs, Solveiga Grinberga, Maija Dambrova, Edgars LiepinshAbstract:Extremely multiresistant strains of Enterobacteriaceae are emerging and spreading at a worrisome pace. Polymyxins are used as the last-resort therapy against such strains, in spite of their nephrotoxicity. We have previously shown that novel Polymyxin Derivatives NAB739 and NAB815 are less nephrotoxic in cynomolgus monkeys than Polymyxin B and are therapeutic in murine Escherichia coli pyelonephritis at doses only one-tenth of that needed for Polymyxin B. Here we evaluated whether the increased efficacy is due to increased excretion of NAB739 in urine. Mice were treated with NAB739 and Polymyxin B four times subcutaneously at doses of 0.25, 0.5, 1, 2, and 4 mg/kg. In plasma, a clear dose–response relationship was observed. The linearity of Cmax with the dose was 0.9987 for NAB739 and 0.975 for Polymyxin B. After administration of NAB739 at a dose of 0.25 mg/kg, its plasma concentrations at all tested time points were above 0.5 µg/mL while after administration at a dose of 0.5 mg/kg its plasma concentrations exceeded 1 µg/mL. The Cmax of NAB739 in plasma was up to 1.5-times higher after single (first) administration and up to two-times higher after the last administration when compared to Polymyxin B. Polymyxin B was not detected in urine samples even when administered at 4 mg/kg. In contrast, the concentration of NAB739 in urine after single administration at a dose of 0.25 mg/kg was above 1 µg/mL and after administration of 0.5 mg/kg its average urine concentration exceeded 2 µg/mL. At the NAB739 dose of 4 mg/kg, the urinary concentrations were higher than 35 µg/mL. These differences explain our previous finding that NAB739 is much more efficacious than Polymyxin B in the therapy of murine E. coli pyelonephritis.
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the Polymyxin Derivative nab739 is synergistic with several antibiotics against Polymyxin resistant strains of escherichia coli klebsiella pneumoniae and acinetobacter baumannii
Peptides, 2019Co-Authors: Jonathan M. Tyrrell, Timo Vaara, Ali F Aboklaish, Timothy R Walsh, Martti VaaraAbstract:The antibiotic crisis has reinstated Polymyxins, once abandoned because of their toxicity. Now, preclinical studies have revealed better tolerated and more effective Derivatives of Polymyxins such as NAB739. Simultaneously, Polymyxin-resistant (PMR) strains such as the mcr-1 strains have received lots of justified publicity, even though they are still very rare. Here we show that NAB739 sensitizes the PMR strains to rifampin, a classic “anti-Gram-positive” antibiotic excluded by the intact outer membrane (OM) permeability barrier, as well as to retapamulin, the surrogate of lefamulin, an antibiotic under development against Gram-positive bacteria. Polymyxin B was used as a comparator. The combination of NAB739 and rifampin was synergistic against ten out of eleven PMR strains of Escherichia coli (Fractional Synergy Indices, FICs, 0.14-0.19) and that of NAB739 and retapamulin against all the tested eleven strains (FICs 0.19-0.25). Against PMR Klebsiella pneumoniae (n = 7), the FICs were 0.13-0.27 for NAB739 + rifampin and 0.14-0.28 for NAB739+retapamulin. Against Acinetobacter baumannii (n = 2), the combination of NAB739 and rifampin had the FIC of 0.09-0.19. Furthermore, NAB739 and meropenem were synergistic (FICs 0.25-0.50) against four out of five PMR strains that were simultaneously resistant to meropenem.
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Structure–activity studies on Polymyxin Derivatives carrying three positive charges only reveal a new class of compounds with strong antibacterial activity
Peptides, 2017Co-Authors: Martti Vaara, Timo Vaara, Jonathan M. TyrrellAbstract:Recent years have brought in an increased interest to develop improved Polymyxins. The currently used Polymyxins, i.e. Polymyxin B and colistin (Polymyxin E) are pentacationic lipopeptides that possess a cyclic heptapeptide part with three positive charges, a linear “panhandle” part with two positive charges, and a fatty acyl tail. Unfortunately, their clinical use is shadowed by their notable nephrotoxicity. We have previously developed a Polymyxin Derivative NAB739 which lacks the positive charges in the linear part. This Derivative is better tolerated than Polymyxin B in cynomolgus monkeys and is, in contrast to Polymyxin B, excreted into urine in monkeys and rats. Here we have conducted further structure-activity relationship (SAR) studies on 17 Derivatives with three positive charges only. We discovered a remarkably antibacterial class, as exemplified by NAB815, that carries two positive charges only in the cyclic part.
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Antimicrobial activity of the novel Polymyxin Derivative NAB739 tested against Gram-negative pathogens
The Journal of antimicrobial chemotherapy, 2012Co-Authors: Martti Vaara, Helio S. Sader, Paul R. Rhomberg, Ronald N. Jones, Timo VaaraAbstract: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 MIC(90)s 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 MIC(90) was ≥ 64 mg/L. Conclusions The MIC(90) 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 MIC(90) 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 MIC(90) values of NAB739 were high and 2- to 4-fold higher than those of Polymyxin B.
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a novel Polymyxin Derivative that lacks the fatty acid tail and carries only three positive charges has strong synergism with agents excluded by the intact outer membrane
Antimicrobial Agents and Chemotherapy, 2010Co-Authors: Martti Vaara, Osmo Siikanen, Juha Heikki Antero Apajalahti, John E Fox, Niels Frimodtmoller, Anima Poudyal, Roger L Nation, Timo VaaraAbstract: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
Martti Vaara - One of the best experts on this subject based on the ideXlab platform.
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Excretion of the Polymyxin Derivative NAB739 in Murine Urine
Antibiotics (Basel Switzerland), 2020Co-Authors: Martti Vaara, Timo Vaara, Janis Kuka, Eduards Sevostjanovs, Solveiga Grinberga, Maija Dambrova, Edgars LiepinshAbstract:Extremely multiresistant strains of Enterobacteriaceae are emerging and spreading at a worrisome pace. Polymyxins are used as the last-resort therapy against such strains, in spite of their nephrotoxicity. We have previously shown that novel Polymyxin Derivatives NAB739 and NAB815 are less nephrotoxic in cynomolgus monkeys than Polymyxin B and are therapeutic in murine Escherichia coli pyelonephritis at doses only one-tenth of that needed for Polymyxin B. Here we evaluated whether the increased efficacy is due to increased excretion of NAB739 in urine. Mice were treated with NAB739 and Polymyxin B four times subcutaneously at doses of 0.25, 0.5, 1, 2, and 4 mg/kg. In plasma, a clear dose–response relationship was observed. The linearity of Cmax with the dose was 0.9987 for NAB739 and 0.975 for Polymyxin B. After administration of NAB739 at a dose of 0.25 mg/kg, its plasma concentrations at all tested time points were above 0.5 µg/mL while after administration at a dose of 0.5 mg/kg its plasma concentrations exceeded 1 µg/mL. The Cmax of NAB739 in plasma was up to 1.5-times higher after single (first) administration and up to two-times higher after the last administration when compared to Polymyxin B. Polymyxin B was not detected in urine samples even when administered at 4 mg/kg. In contrast, the concentration of NAB739 in urine after single administration at a dose of 0.25 mg/kg was above 1 µg/mL and after administration of 0.5 mg/kg its average urine concentration exceeded 2 µg/mL. At the NAB739 dose of 4 mg/kg, the urinary concentrations were higher than 35 µg/mL. These differences explain our previous finding that NAB739 is much more efficacious than Polymyxin B in the therapy of murine E. coli pyelonephritis.
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the Polymyxin Derivative nab739 is synergistic with several antibiotics against Polymyxin resistant strains of escherichia coli klebsiella pneumoniae and acinetobacter baumannii
Peptides, 2019Co-Authors: Jonathan M. Tyrrell, Timo Vaara, Ali F Aboklaish, Timothy R Walsh, Martti VaaraAbstract:The antibiotic crisis has reinstated Polymyxins, once abandoned because of their toxicity. Now, preclinical studies have revealed better tolerated and more effective Derivatives of Polymyxins such as NAB739. Simultaneously, Polymyxin-resistant (PMR) strains such as the mcr-1 strains have received lots of justified publicity, even though they are still very rare. Here we show that NAB739 sensitizes the PMR strains to rifampin, a classic “anti-Gram-positive” antibiotic excluded by the intact outer membrane (OM) permeability barrier, as well as to retapamulin, the surrogate of lefamulin, an antibiotic under development against Gram-positive bacteria. Polymyxin B was used as a comparator. The combination of NAB739 and rifampin was synergistic against ten out of eleven PMR strains of Escherichia coli (Fractional Synergy Indices, FICs, 0.14-0.19) and that of NAB739 and retapamulin against all the tested eleven strains (FICs 0.19-0.25). Against PMR Klebsiella pneumoniae (n = 7), the FICs were 0.13-0.27 for NAB739 + rifampin and 0.14-0.28 for NAB739+retapamulin. Against Acinetobacter baumannii (n = 2), the combination of NAB739 and rifampin had the FIC of 0.09-0.19. Furthermore, NAB739 and meropenem were synergistic (FICs 0.25-0.50) against four out of five PMR strains that were simultaneously resistant to meropenem.
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Structure–activity studies on Polymyxin Derivatives carrying three positive charges only reveal a new class of compounds with strong antibacterial activity
Peptides, 2017Co-Authors: Martti Vaara, Timo Vaara, Jonathan M. TyrrellAbstract:Recent years have brought in an increased interest to develop improved Polymyxins. The currently used Polymyxins, i.e. Polymyxin B and colistin (Polymyxin E) are pentacationic lipopeptides that possess a cyclic heptapeptide part with three positive charges, a linear “panhandle” part with two positive charges, and a fatty acyl tail. Unfortunately, their clinical use is shadowed by their notable nephrotoxicity. We have previously developed a Polymyxin Derivative NAB739 which lacks the positive charges in the linear part. This Derivative is better tolerated than Polymyxin B in cynomolgus monkeys and is, in contrast to Polymyxin B, excreted into urine in monkeys and rats. Here we have conducted further structure-activity relationship (SAR) studies on 17 Derivatives with three positive charges only. We discovered a remarkably antibacterial class, as exemplified by NAB815, that carries two positive charges only in the cyclic part.
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Antimicrobial activity of the novel Polymyxin Derivative NAB739 tested against Gram-negative pathogens
The Journal of antimicrobial chemotherapy, 2012Co-Authors: Martti Vaara, Helio S. Sader, Paul R. Rhomberg, Ronald N. Jones, Timo VaaraAbstract: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 MIC(90)s 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 MIC(90) was ≥ 64 mg/L. Conclusions The MIC(90) 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 MIC(90) 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 MIC(90) values of NAB739 were high and 2- to 4-fold higher than those of Polymyxin B.
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a novel Polymyxin Derivative that lacks the fatty acid tail and carries only three positive charges has strong synergism with agents excluded by the intact outer membrane
Antimicrobial Agents and Chemotherapy, 2010Co-Authors: Martti Vaara, Osmo Siikanen, Juha Heikki Antero Apajalahti, John E Fox, Niels Frimodtmoller, Anima Poudyal, Roger L Nation, Timo VaaraAbstract: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
Jonathan M. Tyrrell - One of the best experts on this subject based on the ideXlab platform.
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the Polymyxin Derivative nab739 is synergistic with several antibiotics against Polymyxin resistant strains of escherichia coli klebsiella pneumoniae and acinetobacter baumannii
Peptides, 2019Co-Authors: Jonathan M. Tyrrell, Timo Vaara, Ali F Aboklaish, Timothy R Walsh, Martti VaaraAbstract:The antibiotic crisis has reinstated Polymyxins, once abandoned because of their toxicity. Now, preclinical studies have revealed better tolerated and more effective Derivatives of Polymyxins such as NAB739. Simultaneously, Polymyxin-resistant (PMR) strains such as the mcr-1 strains have received lots of justified publicity, even though they are still very rare. Here we show that NAB739 sensitizes the PMR strains to rifampin, a classic “anti-Gram-positive” antibiotic excluded by the intact outer membrane (OM) permeability barrier, as well as to retapamulin, the surrogate of lefamulin, an antibiotic under development against Gram-positive bacteria. Polymyxin B was used as a comparator. The combination of NAB739 and rifampin was synergistic against ten out of eleven PMR strains of Escherichia coli (Fractional Synergy Indices, FICs, 0.14-0.19) and that of NAB739 and retapamulin against all the tested eleven strains (FICs 0.19-0.25). Against PMR Klebsiella pneumoniae (n = 7), the FICs were 0.13-0.27 for NAB739 + rifampin and 0.14-0.28 for NAB739+retapamulin. Against Acinetobacter baumannii (n = 2), the combination of NAB739 and rifampin had the FIC of 0.09-0.19. Furthermore, NAB739 and meropenem were synergistic (FICs 0.25-0.50) against four out of five PMR strains that were simultaneously resistant to meropenem.
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Structure–activity studies on Polymyxin Derivatives carrying three positive charges only reveal a new class of compounds with strong antibacterial activity
Peptides, 2017Co-Authors: Martti Vaara, Timo Vaara, Jonathan M. TyrrellAbstract:Recent years have brought in an increased interest to develop improved Polymyxins. The currently used Polymyxins, i.e. Polymyxin B and colistin (Polymyxin E) are pentacationic lipopeptides that possess a cyclic heptapeptide part with three positive charges, a linear “panhandle” part with two positive charges, and a fatty acyl tail. Unfortunately, their clinical use is shadowed by their notable nephrotoxicity. We have previously developed a Polymyxin Derivative NAB739 which lacks the positive charges in the linear part. This Derivative is better tolerated than Polymyxin B in cynomolgus monkeys and is, in contrast to Polymyxin B, excreted into urine in monkeys and rats. Here we have conducted further structure-activity relationship (SAR) studies on 17 Derivatives with three positive charges only. We discovered a remarkably antibacterial class, as exemplified by NAB815, that carries two positive charges only in the cyclic part.
Minh-duy Phan - One of the best experts on this subject based on the ideXlab platform.
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Repurposing a neurodegenerative disease drug to treat Gram-negative antibiotic-resistant bacterial sepsis.
Science translational medicine, 2020Co-Authors: David M. P. De Oliveira, Lisa Bohlmann, Trent Conroy, Freda E.-c. Jen, Arun V. Everest-dass, Karl A. Hansford, Raghu Bolisetti, Ibrahim M. El-deeb, Brian M. Forde, Minh-duy PhanAbstract:The emergence of Polymyxin resistance in carbapenem-resistant and extended-spectrum β-lactamase (ESBL)-producing bacteria is a critical threat to human health, and alternative treatment strategies are urgently required. We investigated the ability of the hydroxyquinoline analog ionophore PBT2 to restore antibiotic sensitivity in Polymyxin-resistant, ESBL-producing, carbapenem-resistant Gram-negative human pathogens. PBT2 resensitized Klebsiella pneumoniae, Escherichia coli, Acinetobacter baumannii, and Pseudomonas aeruginosa to last-resort Polymyxin class antibiotics, including the less toxic next-generation Polymyxin Derivative FADDI-287, in vitro. We were unable to select for mutants resistant to PBT2 + FADDI-287 in Polymyxin-resistant E. coli containing a plasmid-borne mcr-1 gene or K. pneumoniae carrying a chromosomal mgrB mutation. Using a highly invasive K. pneumoniae strain engineered for Polymyxin resistance through mgrB mutation, we successfully demonstrated the efficacy of PBT2 + Polymyxin (colistin or FADDI-287) for the treatment of Gram-negative sepsis in immunocompetent mice. In comparison to Polymyxin alone, the combination of PBT2 + Polymyxin improved survival and reduced bacterial dissemination to the lungs and spleen of infected mice. These data present a treatment modality to break antibiotic resistance in high-priority Polymyxin-resistant Gram-negative pathogens.
Roger L Nation - One of the best experts on this subject based on the ideXlab platform.
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a novel Polymyxin Derivative that lacks the fatty acid tail and carries only three positive charges has strong synergism with agents excluded by the intact outer membrane
Antimicrobial Agents and Chemotherapy, 2010Co-Authors: Martti Vaara, Osmo Siikanen, Juha Heikki Antero Apajalahti, John E Fox, Niels Frimodtmoller, Anima Poudyal, Roger L Nation, Timo VaaraAbstract: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
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A novel Polymyxin Derivative that lacks the fatty acid tail and carries only three positive charges has strong synergism with agents excluded by the intact outer membrane.
Antimicrobial agents and chemotherapy, 2010Co-Authors: Martti Vaara, Osmo Siikanen, Juha Heikki Antero Apajalahti, John E Fox, Anima Poudyal, Roger L Nation, Niels Frimodt-møller, Timo VaaraAbstract: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