Modified Polymyxin Compounds Reducing Nephrotoxicity
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Solution Overview
Problem
Current polymyxin derivatives used to treat Gram-negative bacterial infections often exhibit nephrotoxicity and variable biological activity, limiting their therapeutic efficacy and safety.
Innovation Solution
Development of polymyxin compounds with modified N-terminal groups containing hydroxyl and/or amino functionality, which reduce toxicity and enhance antimicrobial activity against Gram-negative bacteria, including strains resistant to polymyxin B and colistin.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If polymyxin derivatives are used to treat Gram-negative bacterial infections, then antimicrobial activity is achieved, but nephrotoxicity occurs
Solution Approach 1:
The patent modifies the chemical structure of polymyxin derivatives by changing parameters such as the N-terminal group composition, fatty acyl chain length, and amino acid sequence. Specifically, it uses polymyxin derivatives with modified N-terminal groups (formula I and II) that contain hydroxyl and/or amino functionality, which reduces nephrotoxicity while maintaining antimicrobial activity against Gram-negative bacteria.
Solution Approach 2:
The patent applies local quality modification by selectively altering specific regions of the polymyxin molecule, particularly the N-terminal end and fatty acyl chains. By modifying these specific local areas while maintaining the core polymyxin structure, the compound retains its ability to bind to gram-negative bacteria while reducing harmful effects on the kidneys.
2Reliability
If polymyxin B and colistin are used for treatment, then activity against Gram-negative bacteria is achieved, but variable biological activity and toxicity limit therapeutic efficacy
Solution Approach 1:
The patent systematically varies multiple parameters including the N-terminal group structure (hydroxyl-containing groups, amino-containing groups), fatty acyl chain length (C6-C18), and core polymyxin sequence to create a series of derivatives with optimized and consistent biological activity across different Gram-negative bacterial strains.
Solution Approach 2:
The patent develops polymyxin derivatives that achieve universal effectiveness against a broad range of Gram-negative bacteria, including multidrug-resistant strains. The modified structure enables the compounds to function effectively against diverse pathogens such as E. coli, K. pneumoniae, P. aeruginosa, and A. baumannii, providing versatile therapeutic coverage.
Data Source
AI summary
The present invention provides a compound of formula (I), and its use in methods of treatment, including the treatment of bacterial infections. Methods for the preparation of the compound of formula (I) are also provided. The compound of formula (I) has the structure shown below, where —R6 and —R7 are each together with the carbonyl group and nitrogen alpha to the carbon to which it is attached an amino acid residue, except that R6 together with the carbonyl group and nitrogen alpha to the carbon to which it is attached is not a phenylalanine, leucine or valine residue and/or —R7 together with the carbonyl group and nitrogen alpha to the carbon to which it is attached is not a leucine, iso-leucine, phenylalanine, threonine, valine or nor-valine residue, and -T, -A1, -A2, -A3 and —R10 are as discussed in the application: