Polymyxin Derivative NAB815 Reduces Nephrotoxicity
Solution Overview
Problem
Current polymyxin antibiotics are effective against Gram-negative bacteria but suffer from severe nephrotoxicity, limiting their therapeutic use due to high systemic toxicity and suboptimal dosage regimens that increase adverse effects.
Innovation Solution
Development of polymyxin derivatives, such as NAB815, which carry only three positive charges and have a unique amino acid sequence, reducing nephrotoxicity while maintaining high antibacterial activity, and are excreted in urine to enhance therapeutic efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If polymyxin antibiotics are used to treat Gram-negative bacteria, then antibacterial activity is improved, but nephrotoxicity increases
Solution Approach 1:
The patent modifies the chemical structure of polymyxin by changing the number of positive charges from five to three through specific amino acid substitutions. This parameter change in the molecular structure reduces nephrotoxicity while preserving antibacterial activity against Gram-negative bacteria, directly resolving the contradiction between efficacy and toxicity.
Solution Approach 2:
The invention introduces specific local modifications to the polymyxin molecule by substituting particular amino acid residues (e.g., replacing basic amino acids with non-basic or acidic ones at specific positions). These localized structural changes reduce the overall positive charge density in critical regions, thereby reducing kidney toxicity while maintaining the antibiotic's ability to bind to and kill bacteria.
2Reliability
If larger doses of polymyxin are administered to overcome suboptimal serum concentrations, then therapeutic efficacy is improved, but nephrotoxicity increases
Solution Approach 1:
By fundamentally changing the molecular parameter of positive charge count from five to three, the derivative achieves better therapeutic index. This allows effective treatment at lower doses, avoiding the nephrotoxicity associated with higher dosing of conventional polymyxins, thus resolving the dose-dependent contradiction between efficacy and safety.
3Object-affected harmful factors
If polymyxin derivatives with reduced positive charges are developed, then nephrotoxicity is reduced, but antibacterial activity may be compromised
Solution Approach 1:
The patent applies local quality modification by strategically placing charge-reducing amino acid substitutions at specific positions in the polymyxin sequence while preserving critical regions for bacterial binding. This selective local modification maintains antibacterial activity through preserved key interaction sites while reducing overall toxicity, resolving the contradiction between reduced charges and maintained efficacy.
Solution Approach 2:
The invention carefully controls the parameter change by reducing positive charges from five to three (not eliminating them completely), maintaining the cationic character necessary for binding to negatively charged bacterial membranes while reducing excessive charge-related toxicity. This optimized parameter change resolves the contradiction between charge reduction and activity preservation.
Data Source
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AI summary
The present invention relates to a polymyxin derivative of formula (I) and pharmaceutically acceptable salts thereof. The invention further relates to their use in the treatment of a bacterial infection, in particular infections caused by Gram-negative bacteria.