Polymyxin Compounds Reducing Nephrotoxicity
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Solution Overview
Problem
Current antibiotics, such as polymyxins, used to treat Gram-negative bacterial infections often exhibit nephrotoxicity, limiting their use and necessitating the development of alternatives with reduced toxicity while maintaining antibacterial efficacy.
Innovation Solution
Development of polymyxin type compounds with 4 or more positive charges, specifically designed with peptide structures that include certain amino acid residues and alkyl or cycloalkyl substituents, which reduce toxicity by disrupting hydrophobicity and membrane alignment, thereby reducing residency time in kidney cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If polymyxin antibiotics are used to treat Gram-negative bacterial infections, then antibacterial efficacy is improved, but nephrotoxicity increases
Solution Approach 1:
The patent applies parameter changes by modifying the charge number of polymyxin derivatives. Specifically, it develops compounds with 4 or more positive charges (such as polymyxin B1 with 5 charges and colistin with 4 charges) instead of the conventional 2-3 charges. This parameter change in molecular charge density enables the compounds to maintain strong antibacterial activity against Gram-negative bacteria while reducing nephrotoxicity, as the higher charge density disrupts hydrophobicity and membrane alignment in kidney cells, reducing residency time
Solution Approach 2:
The patent creates composite molecular structures by combining multiple amino acid residues with specific alkyl or cycloalkyl substituents bearing hydroxyl groups or amino groups. The compounds incorporate nine specific amino acid residues (phenylalanine, leucine, valine, threonine, α,γ-diaminobutyric acid, serine) combined with charged substituents (R5 groups), forming a composite structure that achieves both high antibacterial efficacy and reduced nephrotoxicity through the synergistic effect of the peptide backbone and charged side chains
2Object-affected harmful factors
If polymyxin derivatives with 2-3 positive charges are used, then nephrotoxicity is reduced, but antibacterial activity may be compromised
Solution Approach 1:
The patent inverts the conventional approach by increasing rather than decreasing the number of positive charges. Instead of reducing charge from 4+ to 2-3+ to lower toxicity, it maintains 4 or more charges (5 in polymyxin B1, 4 in colistin) while achieving reduced nephrotoxicity through the specific arrangement and type of charged groups, thereby inverting the traditional trade-off relationship between charge density and toxicity
Data Source
AI summary
Provided are compounds, the use of the said compounds in treatment, for example treatment of microbial infections, particularly by Gram negative bacteria. The compounds are polymyxin-based and are represented by the formula (I):and pharmaceutically acceptable salts thereof, where X is —NHC(O)—, —C(O)—, —OC(O)—, —CH2— or —SO2—; R5 represents C0-12 alkyl(C4-6 heterocyclyl), or C2-12 alkyl or C0-12 alkyl(C3-8 cycloalkylyl). and the alkyl or cycloalkylyl bears one, two or three hydroxyl groups, or a —NR6R7 group, or one —NR6R7 group and one or two hydroxyl groups; and R1 to R4 and R6 to R8 are as defined in the description.