Polymyxin Derivatives Charge Optimization for Reduced Toxicity
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Solution Overview
Problem
Current treatments for bacterial infections, particularly those caused by multiresistant Gram-negative bacteria, are inadequate due to the toxicity of polymyxin antibiotics and the limited effectiveness of other antibiotics against these pathogens.
Innovation Solution
Development of polymyxin derivatives with two to three positive charges, which retain antibacterial activity and the ability to sensitize bacteria to other antibiotics, reducing toxicity and improving pharmacokinetic properties.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If polymyxin antibiotics are used to treat Gram-negative bacterial infections, then antibacterial effectiveness is improved, but toxicity increases
Solution Approach 1:
The patent modifies the charge parameter of polymyxin antibiotics by creating derivatives with reduced positive charge density (2-3 charges per molecule compared to 4-6 in natural polymyxins). This parameter change maintains antibacterial effectiveness against Gram-negative bacteria while reducing toxicity to host tissues, particularly nephrotoxicity and neurotoxicity.
Solution Approach 2:
The patent segments the polymyxin molecule into functional components, separating the cationic peptide portion (residues 2-7) from the fatty acid tail (residue 1). This segmentation allows independent optimization of the peptide chain to reduce overall charge while maintaining the disruptive effect on bacterial outer membranes, thereby reducing toxicity without sacrificing antibacterial activity.
2Object-affected harmful factors
If polymyxin derivatives with reduced charge are developed, then toxicity is reduced, but antibacterial activity may be compromised
Solution Approach 1:
The patent applies local quality by concentrating positive charges in specific locations within the peptide structure rather than distributing them uniformly. The cationic residues are strategically positioned to interact with negatively charged lipopolysaccharide molecules in the bacterial outer membrane, ensuring effective disruption of the membrane structure while reducing overall molecular charge and associated toxicity.
3Reliability
If polymyxins are used as last-resort therapy for multiresistant bacteria, then treatment effectiveness is improved, but adverse effects increase
Solution Approach 1:
The patent converts the harmful high charge density of natural polymyxins into a beneficial property by retaining sufficient positive charges (2-3 per molecule) to effectively disrupt the negatively charged bacterial outer membrane. This converted charge density is just enough to maintain potent antibacterial activity against multiresistant Gram-negative bacteria while being low enough to minimize adverse effects in host tissues.
Data Source
AI summary
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.