Polymixin derivative and application thereof

A technology of polymyxin and derivatives, applied in the direction of polymyxin, antibacterial drugs, drug combinations, etc., can solve the problem of undisclosed bacteria's ability to sensitize antibiotics

Active Publication Date: 2013-04-24
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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  • Polymixin derivative and application thereof
  • Polymixin derivative and application thereof
  • Polymixin derivative and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0196] peptide synthesis

[0197] 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.

[0198] 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.

[0199] Thus, the alpha amino functi...

Embodiment 2

[0210] The compound has direct antibacterial activity against Escherichia coli

[0211] The peptides synthesized in Example 1, each having at least 2 but not more than 3 positive charges, were investigated for their ability to inhibit the growth of E. coli. The assay was performed using LB agar (LBAgar Lennox, Difco, BD, Sparks, MD, USA) plates. The indicator organism E. coli IH3080 (K1:018) is an encapsulated strain originally isolated from a neonate with meningitis (Vaara et al., 1984) and obtained from the National Institute of Public Health (Helsinki, Finland).

[0212] From an overnight grown culture of IH3080 on LB agar made approximately 10 8 cells / ml suspension. 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 the suspension was removed by using a Pasteur pipette. After the surface had dried, small holes (2 m...

Embodiment 3

[0224] Direct antibacterial activity of selected NAB compounds against Acinetobacter Baumea and Pseudomonas aeruginosa

[0225] The direct antibacterial activity of 12 NAB compounds against Acinetobacter boumee ATCC 19606 and Pseudomonas aeruginosa ATCC 27853 was determined by using the susceptibility assay described in Example 2. The results are shown in Table 3. Five compounds (NAB7062, NAB734, NAB737, NAB739, and NAB740) had significant activity against Acinetobacter permea. In Example 2, the same compound was shown to be very effective against E. coli. The antibacterial activity of NAB739 and NAB740 was comparable or even stronger than polymyxin B.

[0226] Against Pseudomonas aeruginosa, the most active NAB compounds were NAB739, NAB740 and NAB736 with little activity against Escherichia coli and A. NAB740 was the most active compound, as active as polymyxin B. All three NAB compounds lacked positive charges in the side chains and were still resistant to Pseudomonas a...

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Abstract

The present invention relates to a polymixin derivative, wherein R1, R2 and R3 are optional, but unessential, and R1, R2, R3, R5, R8 and R9 represent cationic or neutral amino acid residues specified so that total positive charge at physiological pH value makes at least two, but no more than three. The invention also refers to a method of treating, relieving or suppressing an infection in an individual caused by a gram-negative bacterium, by introducing a therapeutically effective amount of the derivative according to the present invention to the specified individual; to a method of sensitising the gram-negative bacteria to an antibacterial agent by introducing simultaneously or sequentially in any order the therapeutically effective amount of the specified antibacterial agent and the derivative according to the present invention to the specified individual. The invention also relates to a method for developing new antibiotics; reducing nephrotoxicity, improving pharmacokinetic properties of natural polymixins and octapeptines; and sensitising the clinically significant bacteria to the protective mechanism of a host complement found in serum, and also developing a method of producing such polymixin derivatives.

Description

[0001] This application is a divisional application of a Chinese patent application with application number 200780029855.5, and the original application is a Chinese national phase application of the international application PCT / FI2007 / 050441. 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 may have antibacterial effects, or may sensitize bacteria to enhance the effects 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 million Americans develop nosocomial infections each year, 10 percent of which develop ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/62A61K38/12A61P31/04
CPCA61K38/00C07K7/62A61P31/00A61P31/04A61K38/12C12P21/02
Inventor 马尔蒂·瓦拉蒂莫·瓦拉
Owner NORTHERN ANTIBIOTICS
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