Short fatty acid tail polymyxin derivatives and uses thereof

A technology of polymyxins and derivatives, applied in the directions of polymyxins, antibacterial drugs, drug combinations, etc., can solve problems such as the ability of undisclosed bacteria to sensitize to antibiotics

Active Publication Date: 2014-10-08
NORTHERN ANTIBIOTICS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

They do not disclose the ability of the compound to sensitize bacteria to antibiotics

Method used

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  • Short fatty acid tail polymyxin derivatives and uses thereof
  • Short fatty acid tail polymyxin derivatives and uses thereof
  • Short fatty acid tail polymyxin derivatives and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0333] peptide synthesis

[0334] Polymyxin derivatives ("NAB peptides" or "NAB compounds") were synthesized by conventional solid phase chemistry using standard Fmoc protection strategies. The C-terminal amino acid is commercially available pre-attached to the solid phase, which when cleaved from the resin with acid yields the C-terminal carboxylic acid.

[0335] The protection strategy is to use three levels of independent protection—temporary Fmoc protection of the α-amino function, which is removed during the acid cleavage stage; and semi-permanent Fmoc protection covering the reactive side chain function while the cyclization reaction occurs. sexual protection. After the peptide is cleaved from the resin, the C-terminal carboxylic acid reacts with the amino function on the side chain of one of the amino acids to form a cyclic peptide. After the cyclization step, removal of the semi-permanent protecting group yields the NAB peptide.

[0336] Therefore, the alpha amino f...

Embodiment 2

[0348] Activity of compounds against Escherichia coli and Pseudomonas aeruginosa

[0349] The ability of the peptides synthesized in Example 1 (all with only 3 positive charges) to sensitize Escherichia coli to the model antibiotic rifampicin was studied. By using LB agar (LB Agar Lennox, Difco, BD, Sparks, MD, USA) plates as well as LB agar control plates without rifampin were used for this assay.

[0350] The indicator organism Escherichia coli IH3080 (K1:018), an encapsulated strain originally isolated from a neonatal patient with meningitis (Vaara et al., 1984), was obtained from the National Institute of Public Health (Helsinki, Finland).

[0351] A suspension of approximately 108 cells / ml in 0.9% NaCl was made from an overnight growth culture of IH3080 on LB agar. An aliquot of this suspension was then pipetted onto the agar plate and the plate was shaken gently to spread the suspension evenly over the entire surface of the plate. Afterwards, the unabsorbed portion of...

Embodiment 3

[0360] NAB741 sensitizes Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae to multiple antimicrobial agents

[0361] By using Mueller-Hinton agar medium (Product No. LabO39; LabM Ltd., Bury, Lancs, UK) in the presence and absence of NAB741 (4 μg / ml), the effect of a representative set of clinically applied antimicrobial agents on two strains of Escherichia coli (ATCC25922 and IH3080), Klebsiella pneumoniae ATCC13883 and Enterobacter cloacae ATCC23355 minimum inhibitory concentration (MIC). MIC was determined by using E-strips (Biodisk Ltd., Solna, Sweden) according to the manufacturer's instructions. The concentration of NAB741 used did not by itself inhibit the growth of the target bacteria. The MICs of NAB741 against all these strains were >16ug / ml.

[0362] The results are shown in Table 3. NAB741 was able to sensitize test strains to rifampicin by a factor of >64 to >2000 at a concentration of 4 μg / ml. The sensitization factor was defined as the ratio o...

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Abstract

The 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; and to a combination product comprising at least two such derivatives. The invention further relates 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 invention to said subject; to methods for developing novel antibiotics; and for sensitizing clinically important bacteria to a host defense mechanism complement present in serum. 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.

Description

[0001] This application is a divisional application of the application number 200980109086.9 and the title of the invention is "short-chain fatty acid tail polymyxin derivatives and their uses". The parent application is the PCT application PCT / FI2009 / 050093 entry into the Chinese national phase application. technical field [0002] The present invention relates to polymyxin derivatives and their use in the treatment of infections caused by Gram-negative bacteria. The polymyxin derivatives of the present invention are particularly suitable for sensitizing bacteria to enhance the effect of other antibacterial agents. Background technique [0003] Sepsis kills more than 215,000 Americans each year. An estimated 750,000 Americans contract severe sepsis each year, and 29% die. Sepsis deaths account for 9% of all deaths in the United States. In the United States, sepsis kills as many people as heart muscle infections and more than traffic accidents. [0004] Two to three mil...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/62A61K38/12A61P31/04
CPCA61K38/00C07K7/62A61P31/04A61P43/00Y02A50/30
Inventor 马尔蒂·瓦拉蒂莫·瓦拉
Owner NORTHERN ANTIBIOTICS
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