Polymyxin derivatives and uses thereof

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 ...

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