Polymyxin derivatives and uses thereof
The present invention relates to a polymyxin derivative 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 defense mechanism complement present in serum. Finally, the invention relates to a process for preparing such polymyxin derivatives.
1. A polymyxin derivative comprising OA-Thr-Ser-cy[Dab-Dab-DPhe-Leu-Dab-Dab-Thr-].
2. A polymyxin derivative comprising OA-Thr-Asn-cy[Dab-Dab-DPhe-Leu-Dab-Dab-Thr-].
3. The polymyxin derivative of claim 1 or 2 , wherein said polymyxin derivative possesses antibacterial activity against Gram-negative bacteria, and/or possesses the ability to sensitize Gram-negative bacteria to antibacterial agents.
4. A combination product comprising a polymyxin derivative comprising OA-Thr-Ser-cy[Dab-Dab-DPhe-Leu-Dab-Dab-Thr-] and a polymyxin derivative comprising OA-Thr-Asn-cy[Dab-Dab-DPhe-Leu-Dab-Dab-Thr-].
5. A pharmaceutical composition comprising the polymyxin derivative of claim 1 or 2 , and at least one pharmaceutically acceptable carrier and/or excipient.
6. The pharmaceutical composition according to claim 5 , further comprising a second antibacterial agent.