Polymyxin derivatives and uses 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: 2009-08-05
NORTHERN ANTIBIOTICS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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  • Polymyxin derivatives and uses thereof
  • Polymyxin derivatives and uses thereof
  • Polymyxin derivatives and uses thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0195] peptide synthesis

[0196] 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.

[0197] 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.

[0198] Thus, the alpha amino functi...

Embodiment 2

[0209] The compound has direct antibacterial activity against Escherichia coli

[0210] 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 (LB Agar 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).

[0211] 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 ...

Embodiment 3

[0223] Direct antibacterial activity of selected NAB compounds against Acinetobacter Baumea and Pseudomonas aeruginosa

[0224] 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.

[0225] 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 polymyxin derivative wherein R1, R2 and R3 are optional and R1, R2, R3, R5, R8 and R9 are cationic or neutral amino acid residues selected so that the total number of positive charges at physiological pH is at least two but no more than three; 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 defence mechanism complement present in serum. Finally, the invention relates to a process for preparing such polymyxin derivatives.

Description

technical field [0001] 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 [0002] 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. [0003] Two to three million American admissions develop nosocomial infections each year, 10% of which develop sepsis. More than 90,000 of these patients died from hospital-acquired sepsis. [0004] According to the 2000 OECD Health Report, severe sepsis and septic shock (severe sepsis with hypotension) claim as many as 135,000 lives each year in the ...

Claims

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Application Information

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